JP2003517997A - Hemostatic polymers useful for rapid blood coagulation and hemostasis - Google Patents

Abstract

  (57) [Summary] A novel hemostatic polymer composition comprising a material containing an uncharged organic hydroxyl group and a material containing at least one of a halogen atom and an epoxy group is provided, which induces rapid blood coagulation and hemostasis at a wound or bleeding site. Features. Methods of using the novel polymer compositions are also provided.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION

This application is related to US Provisional Patent Application No. 60 / 108,18 filed on November 12, 1998.
No. 5 and pending US patent application Ser. No. 09 / 290,8 filed April 13, 1999
No. 46 claims priority and these documents are incorporated herein by reference.

The present invention relates to a novel hemostatic polymer composition containing a substance having an uncharged organic hydroxyl group and a substance having at least one halogen atom and / or epoxy group. This polymer is particularly useful for providing rapid blood coagulation and hemostasis at the wound or bleeding site. Also provided is a method of using this hemostatic polymer.

[0003]

TECHNICAL FIELD OF THE INVENTION

Wound healing involves a complex series of biochemical events in cells that result in the wound contracting, closing, and healing. The wound itself is a traumatic injury to the integrity of the tissue. Wound treatment is intended to protect the wound from further trauma and / or environmental factors that may delay the healing process. Therefore, it has been advocated to promote wound healing by combining systemic and topical approaches, such as the use of antibiotics and the application of appropriate dressings.

The main function of wound dressings is to provide an optimal healing environment by mimicking the natural barrier function of the epithelium. Therefore, in practice, wound dressing requires at least the following. i) suppresses bleeding, ii) isolates and protects the wound or bleeding site from the external environment before healing begins, iii) prevents further contamination and infection by germs, and iv) near the wound surface Keep the microenvironment moist.

[0005] It is generally said that infection at a wound or a bleeding site further damages tissues and promotes inflammation, which impedes wound healing. Such contamination of bacteria may occur due to contact with an infected object, dirt, dust, or bacteria invading the skin of the person himself or herself at the time of injury or later. As a result, the progress of inflammation such as leakage from blood vessels, release and activation of lytic enzymes, generation of free radicals, oxygen consumption, and sensitization of nerve endings of tissues further hinders subsequent healing of wounds. . Thus, it is believed that wound healing can be accelerated by such means, provided that such means do not reduce tissue resistance to infection and basic macrophage function.

In wound management, especially in the military, the control of local bleeding is also very important, as is the case for the general public, such as in the treatment of trauma and commonly performed first aid. Although attempts have been made to control bleeding, conventional bleeding control methods have many drawbacks, as will be explained below.

In the conventional method for controlling local bleeding including extracorporeal bleeding, it is considered preferable to use a cotton gauze pad capable of absorbing 250 ml of blood. The use of such pads is very common in military and especially civilian trauma units. However, cotton pads are generally considered to be passive dressings because they are unable to initiate or promote blood coagulation.

Another method of controlling bleeding (ie closing the wound) is said to be the use of surgical sutures and staples. Although sutures are believed to adequately support the wound, suturing causes additional trauma to the wound site (because the needle and suture must be passed through the tissue), and suturing is time consuming.
In addition, scars may remain ugly on the surface of the skin after the wound is closed. Surgical staples have been developed to improve wound attachment and have improved cosmetic results. It is known that such staples further cause trauma and that staple placement and application requires the use of accessories and often expensive equipment.

Wound healing is a complex process involving factors such as cells, extracellular matrix (ECM) components, and intracellular microenvironment. In particular, wound healing requires the repair or replacement of damaged tissue. The precise nature of such repair or replacement will depend on the organization involved, but such processes necessarily have some basic principles.

By way of background, the formation of blood clots, as part of hemostasis, is often a life-saving process in response to trauma and plays a role in blocking the flow of blood from severed vasculature. . In addition, it may be desirable to initiate or enhance the body's innate hemostatic process. For example, in the case of a serious injury, the victim may need additional assistance to stop or stop the bleeding caused by the trauma.

Blood aggregation occurs by a complex cascade reaction called the aggregation cascade that involves the production of the enzyme thrombin. This thrombin is formed from the interaction of prothrombin with factor Xa, calcium, and other auxiliary substances. An excellent consideration of the hemagglutination cascade is Mann, KG's 17th International Conference on Thrombosis and Hemostasis (XVII Congress of the International Society of Thrombo
sis and Haemostasis), Medscape, 1999. This document is incorporated herein by reference in its entirety.

In wound healing, the final step in the aggregation cascade is the production of insoluble fibrin, which constitutes the insoluble structure of the clot. Fibrin is formed from fibrinogen in the presence of other plasma components, especially thrombin and factor XIII, whereupon thrombin converts fibrinogen and factor XIII to the reactive form.

Thrombin does not exist in the blood circulatory system in an active state, but exists in the form of an inactive precursor, prothrombin. However, thrombin is activated by one of two mechanisms commonly referred to as the extrinsic and intrinsic pathways.
The intrinsic pathway activates thrombin when blood comes into contact with glass outside the body, as seen when blood is placed in a test tube or contacted with other negatively charged surfaces. The extrinsic pathway, on the other hand, activates thrombin when blood contacts injured tissue, producing tissue thromboplastin.

Over the last decade, wound healing processes have advanced tremendously with advances in the understanding of the wound healing process and advances in modern surgical suturing techniques. Such advances have facilitated the use of suitable adjunct materials such as fibrin glue, sealants, and adhesives to facilitate hemostasis while optimizing wound closure status and control. It has also been proposed to use thrombin in the handling of wounds.

The use of exogenous thrombin as a blood clot promoter or hemostatic agent is known in the art. For example, thrombin is commonly used in surgery and emergency situations. Thrombin is topically applied to the wound or bleeding site, typically in the form of a powder or solution. However, the use of thrombin alone as a coagulant and hemostatic agent is limited to small blood clots or injuries; thrombin alone is often inadequate and requires assistance to be effective. .

When bleeding is more advanced or bleeding is extensive, matrices are commonly used that hold thrombin in place to provide the structure for clot formation. Matrix materials known in the art include fibrin foam compositions and gelatinous sponges. However, even in combination with such matrix materials, thrombin is generally believed to be insufficient to induce aggregation and hemostasis against bleeding from arteries.

Another approach to using thrombin as an additive to induce aggregation is to apply thrombin to the wound site along with fractionated plasma.

A therapeutic composition containing fibrinogen and thrombin for use as a tissue or hemostatic agent, an adhesive, or a sequestrant is known (Cronkite EP et al., JA.
MA, 124, 976 (1944), Tidrick RT and Warner ED, Surgery, 15, 90 (19
44)).

Plasma, as the name implies, refers to the liquid portion of blood. The main components of plasma are proteins, anions and cations. Proteins include albumin and globulin. Anions are predominantly chlorides and bicarbonates, and most cations are sodium, potassium, calcium, and magnesium. Plasma also circulates immunoglobulins and some of the components important for clot formation.

Fractionated plasma is obtained from autologous or non-autologous blood sources usually several hours before required, frozen, cryoprecipitated, and thawed before combining with thrombin at the bleeding site.

The advantage of plasma obtained from an autologous blood source is that in using it, there is no need to worry about the transmission of the human virus. However, a drawback of using such formulations is that the bond strength cannot be predicted. Also, the quantity of products available is limited and not immediately available when needed. Therefore, the use of fractionated plasma as an additive to thrombin to promote blood coagulation is very limited, as it must be obtained hours before the plasma is used, usually one day before. . The problem is exacerbated when an emergency occurs and the time difference of several hours required for plasma fractionation is not obtained or is otherwise impractical.

The preferred donor of non-autologous plasma is a non-human mammal. However, recently there is a problem with using blood products obtained from sources that are foreign to the patient, and the risk of transmitting infectious diseases to the patient, thus avoiding the use of non-autologous plasma. ing.

In view of the above, treatments using fibrinogen have been proposed in the prior art, but, like treatments using thrombin, have many drawbacks.

Fibrinogen is a soluble protein found in the plasma of all vertebrates, which upon contact with thrombin polymerizes into an insoluble gel-like network. Fibrinogen in the polymerized state is called fibrin. The conversion of fibrinogen to fibrin is very important in normal hemostasis in vertebrates.

Fibrinogen accounts for 2 to 4 g / liter of plasma proteins. Fibrinogen molecules are monomers, have a molecular weight of about 340,000, and are rod or ellipsoidal particles. Fibrinogen, in a circulating manner, consists of two dimers of the same unit, each unit consisting of three polypeptides known as α, β, and γ. "A" and "B" indicate two small amino terminal peptides known as fibrinopeptide A and fibrinopeptide B, respectively. When fibrinogen A is cleaved from fibrinogen upon conversion of fibrinogen by thrombin, fibrin I
The compound is obtained, which is then cleaved to give the fibrin II compound. The reduction in the molecular weight of fibrinogen due to such cleavage of fibrinopeptides A and B is a very small amount of about 6,000 out of 340,000 daltons, but the polymerization site is exposed.

Fibrinogen proteins have many binding sites that are important for the assembly of the final fibrin network. For a detailed examination of the fibrinogen structure, see Blomba
ck, B., "Fibrinogen and Fibrin Formation and its Role in Fibrinolysis" C
hapter 11, pp. 225-269, in Goldstein, J. ed., Biotechnology of Blood, Bu
See tterworth-Heinemann, Boston, Mass. 1991. Regarding the mechanism of blood aggregation and the structure of fibrinogen, CM Jackson, Ann. Rev. Biochem., 49
: 765-811 (1980) and B. Furie and BC Furie, Cell, 53: 505-518 (1988).

In the last decade, the topical application of fibrin as a surface aggregating agent to initiate hemostasis has become described in the medical community as the use of “fibrin glue”.

Fibrin glue consists of a mixture of human fibrinogen and bovine thrombin and is sold as a kit of fibrinogen and thrombin solutions in separate vials. These solutions are mixed and applied to the wound in various ways, for example as a paste, spray or patch. However, fibrin glue is a less effective remedy for hemostasis. Mixing the patch with the fibrin glue, dipping and coating is a time consuming and tedious task. Potential mistakes can occur in each of the preparation steps, and their effectiveness will therefore depend on the experience of the operator. Furthermore, during the preparation of such solutions, further bleeding occurs, which is washed away by violent bleeding. Although advances have been made in fibrinogen compositions and surgical techniques, these pitfalls in performing hemostasis emphasize the need for the development of suitable products.

Also, the protein has practically limited uses due to physical or chemical properties (eg solubility). U.S. Pat. No. 4,650,678, European Patent No. 0
See 85923 Bl, European patent 085923 B2, and European patent application 085923 A1. All of these documents detail the difficulties of reducing fibrinogen from lyophilized material, the preferred form of fibrinogen for long-term storage for clinical use. Further, US Pat. No. 4,650,678 states that for a fibrinogen solution to be effective as an adhesive composition, it must contain about 80 mg / ml or more of coagulable fibrinogen.

Fibrin glues (sequestrants, adhesives) are based on the basic physiological function of fibrinogen, fibrin-based glues that have proven to be particularly advantageous over non-biological glues are , Mimics the natural aggregation cascade and accelerates the healing process by mimicking the final steps of aggregation, facilitating the formation of fibrin clots.

Conventional fibrin glue / sealants generally consist of concentrated human fibrinogen, bovine aprotinin and factor XIII as the first component, and bovine thrombin and calcium chloride as the second component. When fibrinogen and fibrin-stabilized factor XIII are activated by thrombin in the presence of calcium ions, stable fibrin clots are formed. The most common method of preparing fibrin glue is to simultaneously mix concentrated fibrinogen complex obtained from pooled human blood, bovine thrombin, and ionic calcium immediately before use. Alternatively, these components can be mixed in advance to accelerate the polymerization.

Generally, when these components are applied sequentially to the tissue, the fibrinogen solution is first applied to the tissue. Then, a small amount of highly concentrated thrombin and / or factor XIII solution is applied to the tissue-supported fibrinogen solution to promote aggregation. Usually, to prevent premature lysis and rupture of the applied tissue area,
A fibrinolysis inhibitor is also added. However, this technique is very expensive and complicated because each of the components that make up the adhesive must be separately prepared, stored, and applied. Moreover, this technique is time consuming and difficult to control.

The addition of non-human, especially bovine thrombin, to a fibrin glue formulation used to treat humans exhibits a severe and sometimes fatal anaphylactic reaction. J. Thora
C. Cardiovac. Surg., 105: 892 (1993) reported an hemostatic abnormality caused by an antibody against a bovine protein such as bovine thrombin that cross-reacts with human proteins such as thrombin and factor V. Similarly, a foreign body reaction that occurs after using such fibrin-usisthrombin-containing glue was detected and was reported by Eur. J. Pediatr. Surg.
, 2: 285 (1992). Usis-thrombin is an infectious agent, mad cow (
BSE) and other viral carriers that are pathogenic to mammals are well known. In addition, Usis Thrombin is a potential antigen and may give rise to an immune response in humans. Therefore, use of Usis Thrombin may cause adverse effects on the person who used it (DM Taylor, J. of Hospital Infection, 18 (S
upplement A): 141-146 (1991), SB Prusiner et al., Cornell Vet, 81 No.
2: 85-96 (1991) and D. Matthews, J. Roy. Soc. Health, 3-5 (February 1991).
)).

Further, the fibrinogen used in the fibrin glue is often concentrated from human plasma by cryoprecipitation and precipitation using various reagents such as polyethylene glycol, ether, ethanol, ammonium sulfate, or glycine. That is, there is always the risk of immunogenic reactions to the fibrinogen component of conventional fibrin glue formulations.

For an excellent discussion of fibrin blockers, see M. Brennan, Blood Reviews, 5: 240-2.
44 (1991); JW Gibble and PM Ness, Transfusion, 30: 741-747 (1990); H
. Matras, J. Oral Maxillofac Sura., 43: 605-611 (1985) and R. Lerner and
See N. Binur. J. of Surgical Research, 48: 165-181 (1990). The main problems with the currently used fibrin glue are AIDS, hepatitis B and C in patients treated with fibrin glue / sequestrant from human donors.
It is a risk of transmission of infectious diseases such as hepatitis C (Opth. Surg., 23: 640 (1992)).

As an alternative solution to the above mentioned risk of viral infection, it has been suggested that fibrinogen be obtained from non-human mammalian sources. Fibrinogen compositions that are believed to have been provided by a mammalian species other than human are described in, for example, US Pat. No. 4,377,5.
72 and 4,362,567. However, the therapeutic compositions provided herein are described as containing at least about 70 mg / ml or more of fibrinogen (prior to dilution at the treatment site), and a significant amount of additional antigenic protein impurities. May be present and is associated with a serious risk of an immune response.

In view of the above, practitioners in the art have found that fibrin glues using in-house fibrin,
In other words, it seeks to provide a formulation in which the fibrinogen component of fibrin glue is extracted from the patient's own blood. Infectious diseases such as hepatitis B, non-A, non-B hepatitis, and acquired immunodeficiency syndrome (AIDS) that may be present in the fibrinogen component extracted from pooled human plasma are transmitted. Use of autologous fibrin sequestrants is preferred because they are not dangerous (LE Silverstein et al., Trans
fusion, 28: 319-321 (1988); K. Laitakari and J. Luotonen, Laryngoscope,
99: 974-976 (1989) and A. Dresdale et al., The Annals of Thoracic Surge.
ry, 40: 385-387 (1985)). However, in such a preparation, there is considerable variation in the fibrinogen content due to individual differences of individual patients (donors). Therefore, the use of such formulations has the disadvantage that it is difficult to accurately predict the clinically effective dose. Therefore, the therapeutic value of the use of such formulations is limited.

US Pat. No. 5,185,001 discloses a method of preparing autologous plasma fibrin to induce local hemostasis prior to surgery. Autologous plasma fibrin is then released at the same time as the physiologically acceptable thrombin solution at the treatment site, where hemostasis occurs. Autologous plasma fibrin and thrombin solutions have also been disclosed. The practice of this invention is limited to autologous plasma preparations, which is contrary to the teachings of the present invention.

Heimburger et al., US Pat. No. 5,407,671, European Patent 253198 B1, and European Patent Application Publication No. 25.
3198 A1 discloses a one-component tissue adhesive containing fibrinogen, factor VIII, thrombin inhibitor, prothrombin factor, calcium ions, and optionally other components in an aqueous solution. Heinberger's adhesive can be lyophilized and stored until use. When an adhesive is needed, it is reduced from the freeze-dried solid state to the liquid state by dissolving it in a solvent such as water. The practice of the invention described in this patent requires a combination of various ingredients, which is contrary to the invention.

US Pat. No. 5,330,974 describes tissue adhesives containing fibrinogen, factor XIII, thrombin inhibitors, prothrombin factors, calcium ions, and optionally plasmin inhibitors. . The object of the invention described here is to apply a tissue adhesive to the wound site, in which component of the tissue adhesive acts in cooperation with the promoter originally present in the wound to be adhered. Is released from prothrombin in the adhesive to the thrombin required for adhesion. However, the practice of this patented invention requires a combination of the above components.

US Pat. Nos. 5,804,428, 5,770,194 and 5,76
Nos. 3,411, and 5,750,657 all relate to fibrin sequestrants and their uses. The fibrin compositions disclosed in the above patents may contain some form of fibrin monomer that can be converted into a fibrin polymer. The gist of the invention disclosed in the above patent is thrombin or XIII.
A fibrin composition containing a fibrin I monomer capable of spontaneously forming a fibrin I polymer without using a factor. The resulting Fibrin I polymer functions as a fibrin clot.

Importantly, any source of fibrin I monomer can be used, so long as the resulting fibrin I monomer can be converted to a fibrin I polymer. Sources of the Fibrin I component of this composition include blood and cell cultures that secrete fibrinogen and recombinant fibrinogen, with blood being the preferred source.
The invention disclosed in the above patent is of limited practice in that it requires the isolation of fibrin I from pooled blood sources or patients, in the latter case the risk of transmission of infectious diseases. It's worth knowing that. The inventions of the above patents also differ from the present invention in that they each require a fibrin-based composition that is contrary to the scope of the present invention.

US Pat. Nos. 5,624,669 and 5,575,997 are patents relating to biocompatible monomer compositions (tissue adhesives) and methods of use thereof. The biocompatible monomer composition is represented by the formula CHR = CXY, where X and Y are each a strong electron withdrawing group and R is H. However, when both X and Y are cyano groups,
R is an alkyl group having 1 to 4 carbon atoms. Examples of the inventive monomers disclosed in these two patents include α-cyanoacrylate, which has many drawbacks as shown below.

Further, US Pat. Nos. 5,804,428, 5,770,194, 5,763,411, 5,750,657, and 5,510,102. , No. 4,298,598, No. 4,362,567, No. 4,377,5
No. 72 and No. 4,414,976 also disclose a fibrinogen-containing adhesive composition and a method for preparing the same.

Yet another drawback associated with fibrin glue is that in order to produce an effective glue,
Ingredients must be stored separately until use and thrombin 3
This means that the temperature must be kept below 0 ° C.

In addition, liquid-applied fibrin glues have poor mechanical properties, and formulations containing liquid fibrin glues are time consuming and it is difficult to solubilize thrombin and more importantly fibrinogen.

Furthermore, the fibrin glue cures very quickly in 3 to 5 seconds, but the adhesive strength does not improve even after 5 seconds (J. Biomed. Mater. Res., 26: 481 (1992). )).

To overcome these drawbacks, fast acting surgical adhesives have been proposed in the prior art. One group of such adhesives is α-cyanoacrylate in monomer form.

US Pat. No. 3,527,841 (Wicker et al.), US Pat. No. 3,722,59
No. 9 (Robertson et al.), No. 3,995, 641 (Kronenthal et al.)
, And 3,940,362 (Overhults), which teach the use of α-cyanoacrylates in surgical adhesives. All of these documents are incorporated herein by reference.

Typically when used as an adhesive or blocking agent, the cyanoacrylate is applied in monomeric form to the surface to be bonded or blocked, whereupon anionic polymerization of the monomer typically occurs to produce the desired adhesion. Sexual bond or blockage occurs. Implants such as rods, meshes, screws, and plates can be formed from cyanoacrylate polymers, typically by polymerization with a radical polymerization initiator.

However, α-cyanoacrylate monomers and polymers are potentially dangerous for in vivo use, as they can cause adverse tissue responses. For example, there are reports that methyl α-cyanoacrylate caused tissue inflammation at the site of application.

For example, the use of cyanoacrylate glue as a sealant or adhesive after surgery has a detrimental effect on the tissue in contact with the glue, resulting in necrosis of the tissue and an immune response of the body to foreign substances. I know that. For example, Epstein GH e
See al., Ann. Otol. Rhinol. Laryngol., 95, 40-45 (1986). Similarly, the use of synthetic suture material has been reported to result in tissue ischemia and necrosis.

The adverse tissue response to α-cyanoacrylate is believed to be caused by the products released during biodegradation of polymerized α-cyanoacrylate in vivo. Formaldehyde is the biodegradation product most closely associated with harmful tissue reactions and is said to be particularly relevant to the high concentrations of formaldehyde produced during the rapid biodegradation of polymers. For example Leonard F et al., Journa
l of Applied Polymer Science, Vol. 10, pp. 259-272 (1966); Leonard F. An
nals, New York Academy of Sciences, Vol. 146, pp. 203-213 (1968); Tseng,
Yin-Chao, et al., Journal of Applied Biomaterials, Vol. 1, pp. 111-119
(1990), and Tseng, Yin-Chao, et al., Journal of Biomedical Materials Res.
See earch, Vol. 24, pp. 1355-1367 (1990). In view of the above, α-cyanoacrylate is not widely used for hemostasis.

DEBRISAN is described as a wound cleansing bead and paste and is used to cleanse ulcers and wounds such as venous stasis ulcers, infected traumatic and surgical wounds. It is written that there is. The important thing is to use beads
This means that the wound is limited after it has solidified. Thus, DEBRISAN teaches the opposite of the present invention, with particular emphasis on cleaning wounds as opposed to promoting blood clotting and hemostasis. In addition, the product manual states that "bleeding" is one of the side effects of using it as intended, suggesting that this is not related to blood aggregation or hemostasis. is doing.

None of the above approaches and techniques for inducing blood coagulation and hemostasis are sufficient as providing effective methods for treating and preventing unwanted and excessive blood loss. Is. The most notable drawback is the use of exogenous enzymes to promote the aggregation cascade. Technologies that use autologous or non-autologous blood sources have many drawbacks as well. Importantly, none of the prior art methods teaches a system for the rapid induction of hemostasis without the use of fibrinogen and enzymes.

Therefore, due to the above-mentioned deficiencies in the prior art, it is possible to not only promptly induce blood coagulation and hemostasis at the wound or bleeding site, but also to concentrate the patient's own fibrinogen, which causes exogenous There is an urgent need for a suitable hemostatic polymer composition that can form clots very easily without the need for thrombin.

All patents, patent applications and publications cited herein are hereby incorporated by reference.

[0058]

[Object and Summary of the Invention]

Accordingly, a primary object of the present invention is to provide novel hemostatic polymer compositions for surgery and other medical uses. In the most preferred embodiment, the hemostatic polymer provides immediate hemostasis and allows the clinician to promptly induce hemagglutination at the wound or bleeding site, thus adhering damaged tissue at the wound site quickly and immediately. You can

Another feature of the invention is that the hemostatic polymer composition significantly promotes tissue healing in a cascade-like manner without the use of exogenous thrombin.

The hemostatic polymer composition of the present invention removes fibrinogen from a patient's own blood in vivo.
Since it is concentrated at o, the risk of blood-borne diseases (HIV and hepatitis) can be reduced.

This novel hemostatic polymer composition can eliminate immune responses or significantly reduce the risk.

An embodiment of the present invention is a method of treating a wound or bleeding site in a mammal comprising applying to the wound or bleeding site a therapeutically effective amount of a hemostatic polymer composition,
The hemostatic polymer composition comprises a reaction product of an uncharged substance containing an organic hydroxyl group and a bifunctional substance containing at least one halogen atom or an epoxy group, wherein the bifunctional substance is an organic compound of the uncharged substance. It relates to methods which are reactive with hydroxyl groups.

According to the above method, when the polymer composition comes into contact with blood or bleeding tissue, blood aggregation and hemostasis occur without the addition of exogenous thrombin. Blood aggregation and hemostasis occurs when the hemostatic polymer composition comes into contact with arterial or venous blood flow.

According to another embodiment, a dry, releasable, storage-stable, sterile wound dressing that provides a dry hemostatic zone, wherein the hemostatic agent is within the wound surface and within said hemostatic zone. Wound dressings are provided that include a matrix that includes a hemostatic-promoting amount of a therapeutic agent that accelerates blood aggregation and clot formation at the interface with.

Another method included in the present invention is a method of promoting hemagglutination and hemostasis, which comprises providing a hemostatic polymer composition and a bioreactive agent at a wound or bleeding site with a pharmaceutically effective carrier or diluent. Administration in combination with an agent, wherein the hemostatic polymer composition comprises a reaction product of an uncharged substance containing an organic hydroxyl group and a bifunctional substance containing at least one of a halogen atom or an epoxy group. Is a method that is reactive with organic hydroxyl groups.

According to another feature of the invention, a pharmaceutical composition useful for the rapid induction of hemagglutination and hemostasis, wherein a therapeutically effective amount of a hemostatic polymer is provided as a pharmaceutically acceptable carrier or diluent. The hemostatic polymer comprises a reaction product of an uncharged substance containing an organic hydroxyl group and a bifunctional substance containing at least one of a halogen atom or an epoxy group, the functional group being reactive with the organic hydroxyl group. Is provided.

This pharmaceutical composition may be further combined with a bioactive agent. This living drug is
Antibodies, antigens, antibiotics, wound sterilizers, thrombin, blood coagulation factors, conventional chemotherapeutic or radiotherapeutic agents, VEGF, antitumor agents such as angiostatin and endostatin, biological response modifiers, and these Includes one combination of various combinations. It also includes diagnostic markers.

According to yet another embodiment, a bandage or dressing that induces rapid hemagglutination and hemostasis, the bifunctional comprising an uncharged substance containing an organic hydroxyl group and at least one of a halogen atom or an epoxy group. A bandage or dressing is provided that comprises a therapeutically effective amount of a hemostatic polymer, including a reaction product with a substance, wherein the functional groups are reactive with the organic hydroxyl groups.

The bandage or dressing may have any shape or size depending on how it is used. The dressing itself is preferably flexible so that it can conform to the body surface profile and is in full contact with the wound and the area around it. Wound dressings are preferably in the form of dry powders, gels or porous microspheres.

According to another embodiment of the present invention, a pharmaceutical composition useful for the rapid induction of hemagglutination and hemostasis, comprising a therapeutically effective amount of a hemostatic polymer, said hemostatic polymer containing an organic hydroxyl group. There is provided a composition comprising a reaction product of an uncharged substance comprising a difunctional substance comprising at least one of a halogen atom or an epoxy group, said functional group being reactive with an organic hydroxyl group.

According to yet another embodiment of the present invention, a hemostatic polymer is included in combination with a pharmaceutically acceptable carrier or diluent, said hemostatic polymer comprising an uncharged substance containing an organic hydroxyl group and a halogen atom or There is provided a hemagglutinating wound healing composition comprising a reaction product with a bifunctional material comprising at least one epoxy group, said functional group being reactive with said organic hydroxyl group.

Also included is a hemostatic polymer in combination with a pharmaceutically acceptable carrier or diluent, wherein the hemostatic polymer comprises an uncharged substance containing an organic hydroxyl group and a bifunctional containing at least one of a halogen atom or an epoxy group. A hemagglutinating wound healing composition comprising a reaction product with a substance, wherein said functional group is reactive with said organic hydroxyl group.

The aerosol suspension may further comprise a suitable propellant selected from the group consisting of CO ₂ , nitrogen, air or other suitable propellant.

Yet another embodiment relates to a hemostatic polymer composition further comprising at least one selected from the group consisting of collagen, fibrinogen and thrombin.

The present invention further provides a kit containing the novel hemostatic polymer composition.

The above and other objects, features, and advantages of the present invention will be apparent from the following description.

[0077]

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention the following definitions are used: "Hemostatic polymer composition" also referred to as "hemostatic polymer" means a solution or other formulation which essentially comprises two components: an uncharged organic hydroxyl group. Substances containing,
And a substance containing at least one of a halogen atom and / or an epoxy group. The composition can also be referred to as HP15. HP15 means 1 gram of G-150 that swells to 15 times its original volume when placed in an aqueous environment. Its molecular weight exclusion limit is 3 × 1
It is a value of 0 ⁵ or more. Similarly, HP20 is a modified form of HP15 with a lesser degree of crosslinking. Similarly, its molecular weight exclusion limit is 5 × 10 ⁵ or more.

By “cascade-like effect” is meant a series of reactions that begins with the application of the hemostatic polymers of the present invention to a wound or incision, where the hemostatic polymers rapidly, various coagulation factors and other accessory factors. It triggers the release of substances and initiates the process of physiological coagulation.
Since the polymer is not a substance of the natural plasmin / plasminogen degradation reaction, the hemostatic reaction continues unabated until hemostasis is achieved.

[0079]   “Exogenous thrombin” refers to adding exogenous thrombin to the wound site.

[0080]   "Hemostatic accelerator" also refers to the hemostatic polymer composition of the present invention.

“Hemostatic zone” refers to a suitable matrix containing an effective amount of a hemostatic polymer composition useful for accelerating blood aggregation and clot formation at a wound or bleeding site. It is believed that the formation of coagulum occurs at the interface between the hemostatic zone and the surface of the wound or bleeding site. The formation of coagulum is induced by the polymer composition of the present invention contained in a matrix that forms part of the reagent zone. The dry hemostatic polymer composition of the present invention can be dispersed in the matrix or applied to the surface of the matrix in an amount effective to promote and accelerate blood aggregation.

“Separation matrix” refers to a material that separates the dry hemostatic polymer composition of the present invention from the wound or bleeding site surface, or forms a barrier therebetween.

“Bioactive” refers to a number of immunological, immunochemical or chemical compositions that can be combined with hemostatic polymer compositions. Such compositions include, but are not limited to, antibodies, antigens, antibiotics, wound sterilants, thrombin, blood coagulation factors, chemical and radiotherapeutic agents, gene therapy agents / substances or various of these. Combination. Also included are diagnostic markers. Gene therapy agents can include agents that may be required to revascularize damaged tissue, such as VEGF. Agents such as endostatin and angiostatin are also contemplated as gene therapy agents. Other well-known gene therapy or wound sterilizing agents can be used, including other agents known to those of skill in the art. Any of the above agents can be detectably labeled with a suitable label.

“Rapid hemagglutination” means controlling bleeding at or at a bleeding site as compared to the same wound or bleeding site not benefiting from the polymer composition claimed in this invention. Shows the time it takes for blood clots to form. Surprisingly, the disadvantages associated with conventional methods of topical application of surface aggregating agents such as fibrin, which mimic the final phase of the blood coagulation mechanism, are overcome by using the novel hemostatic polymers of the invention. It was found.

“Co-surface” refers to reaction zone areas and adjacent areas bounded by a wound / bleeding site on one side, substantially on the surface of a three-dimensional hemostatic polymer matrix and areas within space. Including.

“Diagnostic marker” refers to a conventional marker well known to those skilled in the art. By way of example, diagnostic markers are not limited to these exemplifications, but these include detectable labels, including radioactive and non-radioactive labels, and photoactivated labels. Examples of non-radioactive labels include the biotin / avidin system. Diagnostic labels can be useful for monitoring the course of treatment or the wound healing process over time. For example, a hemostatic polymer composition may be complexed with a time-released or biologically inactive detection marker to enter a wound site in vivo, thereby detecting or imaging the wound over time and monitoring its progress. can do.
For example, targeting of the hemostatic polymer composition can be accomplished by the use of a binding agent such as a detectably labeled antibody. The presence of the administered hemostatic polymer composition can be detected in vitro (ie ex vivo) by means known to those of skill in the art.

The present invention is based on the discovery that hemostatic polymer compositions can induce rapid blood coagulation in vivo by concentrating the patient's fibrinogen at the site of the wound or bleeding site. The hemostatic polymer composition that works in concert with concentrated fibrinogen activates the patient's platelets and red blood cells, converting prothrombin to thrombin without the addition of exogenous thrombin. See FIG. It is understood that the use of the hemostatic polymer composition is not intended to be limited to the examples provided below. Indeed, hemostatic polymer compositions are useful for rapid blood aggregation in all mammals, including humans.

Hemostasis is achieved in a cascade-like manner that occurs by the rapid and continuous activation and aggregation of endogenous platelets present in the plasma of patients. Due to this cascade-like effect, the adhesive strength of the hemostatic polymer increases until the maximum adhesive strength is physiologically or beyond the time (3-5 minutes) obtained with fibrin glue and continues until complete hemostasis occurs.

As described in detail below, the novel hemostatic polymer compositions of the present invention have important clinical benefits.

Adhesion of opposing surgically dissected or traumatically lacerated tissue, wound sterilization such as sealants, antibodies, antigens, antibiotics to prevent bleeding or cover open wounds It finds use as a system for delivering therapeutic or other biologically active agents such as substances, analgesics, hormones, conventional chemotherapeutic or radiotherapeutic agents, gene therapy agents / substances, and diagnostic markers. Gene therapy agents can include agents that may be required to revascularize damaged tissue, such as VEGF. Alternatively, agents that interfere with angiogenesis at the wound or bleeding site may also be needed. Therefore, agents such as endostatin and angiostatin are also contemplated as being combinable with the hemostatic polymer compositions of the present invention. The method of combining any one or combination of these with the hemostatic polymer composition is within the ability of one of ordinary skill in the art and need not be described herein.

The hemostatic polymer composition may be used alone or in combination with other hemostatic agents such as collagen, thrombin, cationic polyamino acids, blood coagulation factors, etc. to provide immediate hemostasis in the event of major trauma and bleeding. it can.

Accordingly, one aspect of the invention relates not only to wound healing and hemostasis, but also to healing and regeneration of damaged tissue.

Liquid formulations of polymeric compositions include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. The present invention further contemplates transdermal delivery as another delivery system. It can be in the form of a cream, lotion, and / or emulsion in this case, and can also be included in a matrix or reservoir type transdermal patch conventional for this purpose.

Pharmaceutical forms of the hemostatic compositions suitable for infusion include sterile aqueous solutions or dispersions for the extemporaneous preparation of sterile injectable solutions or dispersions and sterile powders. In all cases, it must be in sterile form and must be of the appropriate fluid to be readily inhaled and expelled with a syringe.

It can be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.

Carriers are, for example, water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycols), suitable mixtures thereof,
Also, a solvent or dispersion solvent containing vegetable oil or the like can be used. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

Solutions of the hemostatic polymer composition can be prepared by methods known to those of ordinary skill in the art. Dispersions can also be prepared with glycerol, liquid polyethylene glycols, and mixtures thereof, and oils. Under ordinary conditions of storage and use, such preparations contain a preservative to prevent the growth of microorganisms.

Microbial activity can be prevented by various antibacterial and antifungal agents such as, for example, paraben, chlorobutanol, phenol, sorbic acid, thimerosal. In many cases, it will be preferable to add isotonic agents, for example sugars or sodium chloride. Absorption of injectable compositions can be prolonged by the use of absorption delaying agents, such as aluminum monostearate and gelatin.

The hemostatic polymer composition is preferably administered as a sterile pharmaceutical composition comprising a pharmaceutically acceptable carrier. This carrier may be any of a number of known carriers such as water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, or combinations thereof. The optimal dose can be determined by administering the hemostatic polymer composition and confirming hemagglutination and hemostasis.

The pharmaceutical compositions used according to the invention may be formulated in a conventional manner with one or more physiologically acceptable carriers containing excipients and auxiliaries, and such carriers may be prepared. Upon use, the active composition can be easily processed into formulations that can be used as medicaments. Proper formulation is dependent upon the route of administration chosen.

For injection, the polymer compositions of the invention are used in aqueous solution, preferably in Hank's solution, Ringer's solution, or physiologically compatible buffers such as saline buffer. It can be formulated. For transmucosal administration, penetrants appropriate for the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

Suitable routes of administration of the polymer composition include, for example, intramuscular, subcutaneous, or intramedullary injection, as well as parenteral delivery such as direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injection. It may be mentioned or administered locally. Alternatively, a pharmaceutical composition comprising the hemostatic polymer composition of the present invention as a major component may be administered locally rather than systemically, for example by injecting the polymer composition directly into a solid tumor. . This can be done with a sustained release formulation.

Preferably, the hemostatic polymer composition is administered using a syringe with two barrels, for example containing the hemostatic polymer composition on one side and thrombin on the other. The two components may be co-administered or mixed prior to administration.

The hemostatic polymer composition has a long storage period and can be stored at room temperature for 2 to 5 years. In addition, the polymer composition can be carried by a person and immediately stop hemostasis in the event of trauma or severe bleeding.

The hemostatic polymer composition of the present invention is prepared by a polymerization process that involves reacting an uncharged organic material containing hydroxyl groups with a bifunctional organic material. Further details on the bifunctional organic material can be found in Swedish Patent No. 865265. The disclosure of this document is incorporated herein by reference.

Briefly, the hemostatic polymer composition is the product of a polymerization process that ultimately forms an insoluble three-dimensional crosslinked polymer network. The three-dimensional network structure of the resulting crosslinked polymer that defines the polymer beads or particles of the hemostatic polymer composition of the present invention comprises an uncharged organic material containing reactive sites for hydroxyl groups and a halogen or epoxy group of a bifunctional organic material. It is formed by reacting. The three-dimensional network of cross-linked polymers can take the form of gels, spheres, fibers, meshes, or nets when applied to a wound or bleeding site. A unique feature of this bead is the presence of a three-dimensional hemostatic cascade reaction zone. This three-dimensional polymer network is further characterized by having no ionized groups and being insoluble in the solvent but swellable in the solvent. The polymer beads of the hemostatic polymer composition are also used in vivo.
Inactive against fibrinogen, a substance isolated in o.

Briefly, the polymer composition is applied directly or with a separation matrix placed between the bleeding wound site and the hemostatic polymer composition. For example, the separation matrix separates the hemostatic polymer composition from direct contact with the surface of the wound or bleeding site.

Without being bound by theory, it is believed that the concentration of plasma proteins (ie fibrinogen and other coagulation factors) causes hemostasis at the site of bleeding. At the beginning of the hemostatic cascade reaction step, the beads are water, saline, saline, depending on the molecular size of the protein and the size of the pores in the three-dimensional polymer network that define the beads of the hemostatic composition.
When plasma or the like is absorbed, low molecular weight components of plasma are absorbed on the surface (first layer) of the polymer beads, and higher molecular weight plasma proteins and fibrinogen are concentrated just outside the first layer. The concentrated fibrinogen then forms a matrix of coagulation factors, both low and high molecular weight coagulation factors, which essentially enclose the beads of the composition and which lead to interstitial spaces between the beads and the wound site. And fill the spaces between the beads. It should be noted that the beads closest to the wound site will form the matrix before those farther away, generally forming a coagulating matrix upon contact with blood.

Basically, the concentrated coagulation factors and hemostatic polymer network trap platelets, which activate the conversion of prothrombin to thrombin in the presence of Ca ⁺⁺ . The charged polymers exposed at the wound site, fibrinogen, and optionally collagen, function as binding sites for platelets and red blood cells (RBCs). Platelets disintegrate and release thromboxane and ADP. This release is due to the coagulation factors Va, Xa
, And Ca ⁺⁺ induce further platelet adhesion. This reaction then initiates the conversion of the patient's prothrombin to thrombin, which hydrolyzes the four Arg-Gly peptide bonds of purified soluble fibrinogen. The resulting long fibrin monomers are responsible for the formation of immediate stable insoluble fibrin clots. As a result, exogenous thrombin is unnecessary.

Suitable hydroxyl-containing substances are polyvinyl alcohols, sugar alcohols, carbohydrates (ie sucrose, sorbitol), polysaccharides (ie dextran, starch, alginates, cellulose), and neutral hydroxyl-containing derivatives of the above compounds. is there.

Suitable bifunctional organic substances for use in preparing the hemostatic polymer composition of the present invention include:
Examples include epichlorohydrin, dichlorohydrin, diepoxy blanc, disepoxy propyl ether, ethylene-glyco-bis-epoxy propyl ether.

The hydroxyl group-containing organic substance and the bifunctional substance are easily copolymerized in an aqueous solution in the presence of an alkaline reaction catalyst. The bifunctional material ideally contains an aliphatic radical of 1 to 10 atoms containing at least one of a halogen and an epoxy reactive group, and forms a three-dimensional crosslinked network structure by reaction with a hydroxyl group.

Reaction of Cross- Linked Polymer with Platelets FIGS. 1 and 1a show the reaction of the cross-linked polymer of the hemostatic polymer composition with platelets at the wound or bleeding site. The reaction of platelets with the crosslinked polymer of the hemostatic polymer composition can be divided into two stages. The first stage is vasoconstriction and the other stage is the formation of platelet plugs.

A. Vasoconstriction First, the cross-linked polymer activates and degranulates the contacting platelets.
At the end of this step, serotonin is released as activated platelets aggregate. Serotonin then contracts the damaged blood vessels as well as adjacent blood vessels within the area.

B. Platelet plug formation In addition to serotonin, platelet activation releases ADP and exposed platelet phosphorides (platelet factors 1, 2, 3, and 4). These platelet-derived phospholipids are very important and serve as a surface for complexing and reacting with coagulation factors. ADP causes platelets to adhere and stick to each other.

In addition, the crosslinked polymer concentrates von Willebrand factor (vWF) in plasma (MW> 800,000) resulting in release from damaged endothelial cells and platelet surfaces. Von Willebrand factor is important for the formation of tight aggregates of platelets and thrombin forms irreversible platelet aggregates (platelet plugs). Reaction of cross-linked polymer and concentration of blood protein The cross-linked polymer beads swell by taking in liquid components in blood such as water, plasma, and blood. Basically, the beads of the present invention are characterized by preventing or eliminating a component of a certain molecular weight from entering the bead and efficiently concentrating the excluded component outside of the bead surface or away from it. And However, this molecular weight exclusion limit depends on the type of blood component absorbed by the beads.

For example, when absorbing water, the exclusion limit is around 300,000, after which the limit is reduced. Similarly, the inclusion of saline reduces the exclusion limit to components with molecular weights below about 200,000. Also, the beads have a molecular weight of about 100,000 when they absorb plasma or blood, for example.
Limit the ingress of the following ingredients: Therefore, the nature of the blood component absorbed by the beads in turn controls the absorption (concentration) of the coagulation factor on the outer periphery of the beads. Thus, depending on the type of components absorbed by the beads of the hemostatic composition at the bleeding site, different types of blood coagulation factors will be absorbed on the bead surface. Basically, the pore size of the polymer network that defines the beads of the composition allows low molecular weight plasma components to enter the beads, thus concentrating low molecular weight plasma proteins primarily at the surface closest to the beads. , Which cooperates with the higher molecular weight components in plasma to subsequently form a three-dimensional coagulation matrix.

Thus, upon contact with a wound or bleeding site, beads of a less hydrated or dried hemostatic polymer composition will have low molecular weight plasma components defined as having a molecular weight of less than 300,000 (<300,000 MW), as well as Efficiently concentrates high molecular weight plasma components such as fibrinogen, which is defined as having a molecular weight above 300,000 (> 300,000 MW), effectively forming a three-dimensional coagulation matrix that basically surrounds the beads of the composition. See, eg, FIG.

A highly concentrated factor I, fibrinogen (molecular weight 340,000), which is basically on the surface of crosslinked polymer beads, then provides the fibrinogen for activating the platelet / coagulation mechanism and converting it to insoluble fibrin. . The concentrated fibrinogen surrounding the crosslinked polymer beads of the hemostatic composition thus acts as a highly negatively charged surface for the binding of Factor XII and the self-activation of the zymogen Factor XII. High molecular weight kininogen (Fitzgerald factor) also binds to the highly negatively charged fibrinogen surface. The presence of small amounts of activated Factor XII activates its substrate, prekallikrein, Factor XI, and polymeric kininogen. Prekallikrein and Factor XI bind to the surface of crosslinked polymers through polymeric kininogen. High molecular weight kininogen also binds to prekallikrein, and factor XI exists as a complex with high molecular weight kininogen, resulting in more prekallikrein factor XI due to activation of cocofactors to increase surface binding. The factor binds to the surface. On the cross-linked polymer surface, activated factor XII cleaves prekallikrein to kallikrein, activating factor XI. Kallikrein can undergo reciprocal activation and generate activated Factor XII. The rate of the cross-linked polymer / concentrated fibrinogen reciprocal activation mechanism is tens of times faster than self-activation.

In summary, the cross-linked polymer is Factor II (prothrombin, molecular weight 70,000), V
Factor (molecular weight 330,000), Factor VII (molecular weight 50,000), Factor VIII (molecular weight 320,
000), factor IX (molecular weight 57,000), factor X (molecular weight 59,000), factor X (molecular weight 59,000), factor XI (molecular weight 143,000), factor XII (molecular weight 76,000), factor XIII
Factor (molecular weight 320,000), polymeric kininogen (Fitzgerald factor, molecular weight 1
20,000-200,000), and prekallikrein (Fletcher factor, molecular weight 85,000)
~ 100,000) to promote hemostasis.

2 and 3 show the surface reactions and coagulation pathways associated with the blood coagulation cascade that result from the administration of the hemostatic polymer composition at the wound or bleeding site. Coagulation Factors A. Intrinsic pathway Factor XII (MW 80,000) is concentrated and activated by cross-linked polymers. The high molecular weight kininogen (Fitzgerald factor, molecular weight 120,000-200,000) is also concentrated and cooperates with Fletcher factor (molecular weight 85,000-100,000) to further activate Factor XII. Factor XII activates Factor XI (molecular weight 143,000),
Initiate the intrinsic pathway of coagulation. Factor XI activates factor IX (57,000 MW) and may require an activated platelet phospholipid surface. Factor IX activation is accelerated by the exogenous Factor VII-TF complex. Factor VIII is highly concentrated by the cross-linked polymer and is activated on the surface of platelet phospholipids complexed with factor X. Thrombin activates factor VIII, factor X, and the platelet phospholipid complex. The intrinsic pathway cooperates with the extrinsic pathway to form a common pathway with activation of factor X.

B. Extrinsic Pathway Cross-linked polymers also concentrate Factor VII (MW 50,000) at the surface of beads. Concentrated factor VII is activated by released endothelial tissue factor. Number V
Factor II is also activated by factors XII and XI activated by the crosslinked polymer. Activated Factor VII also activates Factor X at the end of the extrinsic pathway.

C. Common pathway The intrinsic and extrinsic pathways converge upon activation of factor X. This complex provides a common pathway, facilitating the conversion of concentrated Factor X and Factor II (prothrombin) to activated Factor IIa (thrombin). The most important function of thrombin generated by the endogenous, extrinsic, and common pathways is to separate the two fibrino-peptides from the fibrinogen molecule, leaving rapid fibrin monomers that polymerize to insoluble fibrin.

Thrombin is a cross-linked polymer and activated V on the platelet phospholipid surface.
It has some additional functions such as activation of factors. Factor V is I on the platelet surface
Combines with factor I (prothrombin) to form thrombin. Thrombin activates factor XIII (molecular weight 320,000), which cross-links polymerized fibrin, forming stable fibrin. Thrombin converts the tight aggregation of aggregated platelets into irreversible platelet plugs and fibrin clots.

Bandages on open wounds and similar injuries that secrete or exhale large amounts of body fluid are always a dangerous problem. The wound must be protected from bacterial infections while absorbing the leaking body fluids. Bleeding from blood vessels, body tissues, organs, or bones causes blood loss, leading to hypovolemic shock and death. For hemophiliacs and those who are on anticoagulant therapy often prescribed after heart surgery, rapid blood loss is a more serious problem.

The hemostatic polymer composition, which is the essence of novelty that appears to be patentable, can be applied to wounds in a variety of ways known per se to those skilled in the art. The composition is topically applied to the wound surface or packed within the wound, followed by a protective gauze dressing and the like. Alternatively, the hemostatic polymer composition can be incorporated into a matrix or substrate suitable for application to the wound, for example as a coating, impregnated into the matrix, or by an adhesive.

Accordingly, a removable dry hemostatic zone is provided that can be removed after inducing blood clotting and clot formation at the wound site. The hemostatic zone consists of a suitable matrix containing an effective amount of hemostatic agent. Preferably, the hemostatic agent comprises the hemostatic polymer composition of the present invention. The hemostatic agent may also include an exogenous amount of a blood coagulation composition, such as thrombin, in addition to or in addition to the hemostatic polymer composition of the present invention. Ideally, the hemostatic agent is in dry form. It should be noted that this novel hemostatic zone can be incorporated into any wound dressing, can be a patch, bandage, etc. and can be used to seal open bleeding wounds. The hemostasis zone must contain a hemostasis-promoting amount of a hemostatic agent. The hemostatic agent is preferably the hemostatic polymer composition of the present invention, ideally present in dry form, although the composition can be in other forms.

FIG. 4 shows a plan and side view of a dry, storage stable, sterile, detachable hemostatic zone (12). A wound dressing comprising a substrate (16) having a hemostatic zone (12) is shown in FIG. Here, the base material (16) is a flexible base material such as an adhesive band-aid having a central portion composed of the hemostatic zone (12).

The hemostatic zone (12) of the present invention is effective in the matrix (18) to promote blood coagulation and clot formation at the interface between the wound surface and the hemostatic promoter contained within the hemostatic zone. It is made by applying a hemostatic-promoting amount of a hemostatic agent. Preferably, the hemostatic agent comprises the hemostatic polymer composition of the present invention (hemostatic promoter (20)), the composition comprising an uncharged substance containing an organic hydroxyl group and at least one of a halogen atom or an epoxy group. A reaction product with a bifunctional material, which is reactive with the organic hydroxyl groups of the uncharged material.

Advantageously, the hemostatic polymer composition is applied as a layer, ie by spraying the dry hemostatic polymer composition in powder form onto specific surfaces or sides of the matrix (18). This surface is called a "scratch contact surface". Alternatively, a solution of the hemostatic polymer composition is incorporated on or in the matrix and lyophilized or dried by conventional means.

The dry hemostatic zone of the present invention can be of any known physical form for wound dressing. For example, in one useful form, a backing or cover sheet made of, for example, a polymeric material that provides a barrier to bacteria includes a medical grade pressure sensitive adhesive coating that covers one side, and is an effective reagent of the present invention. Gauze or other suitable matrix containing is placed in the center of the adhesive surface for application over the wound and an uncoated adhesive coating for applying the dressing to the healthy skin around the wound There is an island type dressing in which is left around the matrix.

On the other hand, the hemostatic polymer composition can be placed alone or as part of a hemostatic zone on a solid support that comes into contact with the desired site, such as a bandage, suture, prosthesis, or dressing. . Such a support is then placed in contact with the desired site until, for example, a fibrin clot is formed. Another preferred form is a patch.

It will be appreciated that the removable dry hemostatic zone is applied with the "wound contact" surface of the dressing in contact with the wound or bleeding site surface. The wound dressing is then held in contact with the wound for a time sufficient for coagulation to occur at the interface between the "wound contact surface" and the wound so that bleeding is substantially suppressed. The hemostatic zone is preferably lightly pressured and held against the biological surface. In the matrix /
If the inner reagent zone is used to control bleeding at the wound or bleeding site, the reagent zone can be simply retained by applying pressure to the dressing with gauze or other dry sterile material. Depending on the location of the wound, a bandage such as an elastic bandage may be wrapped around the reagent zone to apply light pressure to the wound site.

Preferably, the wound contact surface of the hemostatic zone is about 4-20 in contact with the wound surface.
Hold for minutes, preferably 4 to 13 minutes, most preferably about 6 to about 10 minutes. The inventors have found that this time zone is sufficient for the reagent zone to promote the patient's blood coagulation cascade and form a clot at the wound or bleeding site. The wound dressing including the hemostatic zone may then be removed and applied to another wound or bleeding site. The same is true for another embodiment of the invention, namely hemostatic patches, bandages, etc. which carry a dry hemostatic zone as a main component on a suitable substrate.

If the hemostatic polymer composition is applied to stabilize the wound site by temporarily suppressing bleeding at the wound site separated from the wound surface by the separating matrix, the time required is preferably about. 5 minutes.

A distinctive feature of dressings with removable dry reagent zones is that unlike conventional glues, as a constituent, fibrinogen, thrombin, or other blood-derived coagulation factors that prevent the entry of unsafe contaminating viruses. It does not require the exogenous human protein.

Furthermore, contrary to the teachings of conventional methods for controlling bleeding at a wound or bleeding site, the removable dry wound dressing of the present invention is removed after promoting clot formation at the wound or bleeding site. , Acts as a removable dry hemostatic zone. This is in sharp contrast to conventional wound treatment methods that leave a hemostatic / composition at the wound or bleeding site, such as a fibrin glue or patch containing glue, to form a clot at the bleeding site. For example, reference is made to a chitosan-containing bandage / wound dressing where chitosan needs to be left at the wound or bleeding site to induce clot formation at the site. In contrast, the spheres of the hemostatic polymer composition, when swollen, become larger than the pores of the matrix that will eventually be removed after a period of time.

A preferred use of the dry hemostatic zone of the present invention is to inhibit or completely stop bleeding in soft tissue organs such as the liver, kidneys, spleen, pancreas, or lungs. Other uses of such a reagent zone, especially the reagent zone which is the main component of the hemostatic patch, include:
For example, during internal / abdominal, vascular (especially anastomosis), euphorical, gynecological (especially perineal incision), thyroid, nervous system, ENT (Ear Nose and Throat), tissue transplantation, and during surgery such as dental surgery. Examples include, but are not limited to, suppressing bleeding from tissues.

The matrix (18) and separation matrix are used interchangeably and include the hemostatic polymer composition (20). Alternatively, the matrix can be a biodegradable "matrix" that can be used in any of this embodiment of the invention, as described herein. The matrix is selected from, but is not limited to, the group consisting of absorbable gelatin sponge, calcium alginate, calcium / sodium alginate, collagen, and oxidized regenerated cellulose. Matrices incorporating esterified or chemically modified collagen are commercially available from Sawyer.
r) in U.S. Pat. No. 4,390,519. This document is incorporated herein by reference. Importantly, other conventional matrices used in hemostatic wound dressings can also be used with the novel hemostatic polymer compositions of the present invention. Alternatively, the matrix is a self-expanding matrix that expands upon contact with the wound site.

An example of an advantageous matrix to which the hemostatic polymer composition and / or other additives according to the present invention may be applied is a compressible matrix. This compressible matrix self-expands on contact with an aqueous medium.

Hemostatic zones also include bacteria, fungi, on the surface of and around the wound or bleeding site,
It is also effective in delaying the contamination by viruses and the growth of mold. This can be done by mixing a biological agent, such as an antibacterial agent, with the hemostatic polymer and then dispersing or applying the resulting mixture to the surface of the matrix.

The reagent zone may further include a biological agent for delivery to the wound or bleeding site. Thus, the reagent zone, alone or in combination with the substrate, provides a mechanical barrier, a microbiological barrier, or a combination thereof. The reagent zones can be in the form of wound dressings, patches, surgical barriers, bandages, or combinations thereof, and can also be used as topical therapeutic formulations for use with conventional dressings, patches, or band aids. You can

[0143] The reagent zone may further contain agents selected for application for topical treatment. The therapeutic drug component of the hemostatic zone may include a single drug, such as the hemostatic polymer composition of the present invention. It is also possible to incorporate the pharmaceutical combination in the reagent zone or in the wound dressing, for example as an additional layer.

Wound dressings are also provided that include suitable substrates carrying / containing the above-described hemostatic zones. A dry wound dressing with a hemostatic zone is the only agent that has an effective amount of a hemostatic agent, preferably a novel dry hemostatic polymer composition, to promote and accelerate the patient's blood coagulation pathway and thus stimulate clot formation. The substance may be contained in a state of being dispersed in the matrix or being applied to the surface of the matrix. Alternatively, wound dressings, such as hemostatic zones, may include additional therapeutic agents.

In one embodiment, the dry wound dressing is contained in a sealed sterile package that allows the patch to be removed without contamination. Such a package may use a bag of aluminum foil or other conventional material that can be easily sterilized, for example. The wound dressing and packing material is sterilized by exposure to radiation, preferably gamma radiation. The same is true for patches with hemostatic zones.

In another embodiment, a container having two compartments is provided. The first compartment contains the separation matrix and the second compartment contains the hemostatic polymer composition in a suitable container such as a syringe. For clinical use, a separation matrix is applied to the wound surface and a syringe containing the dry hemostatic polymer composition is used to reduce or minimize bleeding at the wound site, although separated by the separation matrix. Sufficient time on the wound site to allow the paramedic / surgeon to clearly see the underlying trauma.

Although small cuts, burns, and abrasions are rarely infected, any cleavage in the skin can lead to local or systemic infection. This is especially problematic for children who may not have a fully developed immune system, and for immunocompromised persons. Therefore, the wound dressing of the present invention will also find widespread use in healing wounds in such people.

Wound dressings, which act as hemostatic zones and are intended for topical application, can also be applied by adhesive tape in the form of band-aids with a reagent zone attached to an adhesive backing. Preferably, the adhesive used to secure the patch is porous at the skin contact area. Those skilled in the art will be aware of advances in adhesive tape technology and will not be described here.

One or more additional layers of wound dressing material, preferably a layer that aids in the absorption of blood or other exudates, may also be applied to the reagent zone or bag. Such additional layers can be integrally provided as part of the reagent zone, forming thicker zones. Alternatively, according to the invention, such a layer may be provided on the backside of a wound dressing, such as a patch or flexible bandage or band-aid.
It can also be applied as an aid to the surface that does not come into contact with the wound). In particular for topical use, the layer may be provided with a superabsorbent to carry the exudate from the wound site by capillary action. In the case of wound dressings, including those with additional substrates, such as patches intended for use in endosurgery, the layer is biodegradable and pharmaceutical if the added image is integral with the patch. Note that it must be acceptable.

Therapeutic agents that can be used alone or in combination include anti-inflammatory analgesics, steroidal anti-inflammatory agents, antihistamines, local anesthetics, bactericides and disinfectants,
Vasoconstrictor, hemostatic agent, chemotherapeutic agent, antibiotic, keratolytic agent, corrosive agent, antiviral agent, thrombin, hemostatic agent such as Ca ⁺⁺ , epidermal growth factor (EGF), acidic and basic fibroblasts Examples include, but are not limited to, growth factors (FGFs), wound healing agents such as transforming growth factors α and β (TGF α and β), glycoproteins such as laminin and fibronectin, and various collagens. .

Examples of anti-inflammatory analgesics include: acetaminophen, methyl salicylate, monoglycol salicylate, aspirin, mefenamic acid, flufenamic acid,
Indomethacin, diclofenac, alclofenac, diclofenac sodium, ibuprofen, ketoprofen, naproxen, planoprofen, fenoprofen, sulindac, fenclofenac, klidanac, flurbiprofen, fentiazac, bufexamac, piroxicam, phenylbutazone , Oxyphenbutazone, clofezone, pentazocine, mepyrizole, tiaramide hydrochloride, etc. Steroid anti-inflammatory agents include: hydrocortisone, prednisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, hydrocortisone acetate, prednisolone acetate, methylprednisolone acetate, dexamethasone acetate, betamethasone acetate, betamethasone valerate, flumethasone, fluorometholone, Beclomethasone dipropionate and the like.

Antihistamines include the following: diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine, chlorpheniramine hydrochloride, chlorpheniramine maleate, isothipendyl hydrochloride, triperenamine hydrochloride, promethazine hydrochloride, metizilazine hydrochloride and the like. Examples of local anesthetics include: dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, p-butylaminobenzoic acid 2- (diethylamino) ethyl ester hydrochloride, procaine hydrochloride, tetracaine, tetracaine hydrochloride. , Chloroprocaine hydrochloride, oxyprocaine hydrochloride,
Mepivacaine, cocaine hydrochloride, piperocaine hydrochloride, dyclonine, dyclonine hydrochloride, etc.

Bactericides and disinfectants include the following: thimerosal, phenol, thymol, benzalkonium chloride, benzethonium chloride, chlorohexidine, povidone iodine, cetylpyridinium chloride, eugenol, trimethylammonium bromide and the like. Vasoconstrictors include the following: naphazoline nitrate, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, tramazoline hydrochloride and the like. Examples of hemostatic agents include: thrombin, phytonadione, protamine sulfate,
Aminocaproic acid, tranexamic acid, carbazochrome, carbazochrome sodium sulfanate, rutin, hesperidin, etc.

Examples of chemotherapeutic agents include: sulfamine, sulfathiazole,
Sulfadiazine, homosulfamine, sulfisoxazole, sulfizomidin, sulfamethizole, nitrofurazone and the like. Examples of antibiotics include: penicillin, methicillin, oxacillin, cephalothin, cephalodin, erythromycin, lincomycin, tetracycline, chlortetracycline, oxytetracycline, metacycline, chloramphenicol, kanamycin, streptomycin, gentamicin, bacitracin. , Cycloserine and the like.

Examples of keratolytic agents include salicylic acid, podophyllum, podrifox, and cantharidin. Examples of corrosive agents include chloroacetic acid and silver nitrate. Examples of antiviral agents include: protease inhibitors, thymidine kinase inhibitors, sugar or glycoprotein synthesis inhibitors, structural protein synthesis inhibitors, adhesion and adsorption inhibitors, and acyclovir, penciclovir, valacyclovir, and Nucleoside analogues such as ganciclovir.

The amount of active therapeutic agent (s) used will depend on the therapeutic power desired and the type of area being treated.

In addition, the wound-contacting surface of the wound dressing of the present invention, such as the hemostatic zone, should be coated with a yellow vitamin B ₂ (riboflavin) or a suitable dye such as a color-developing agent such as hemin to assist the user. You can Color coding the wound contact surface allows the user to deliberately avoid touching or contaminating the wound contact surface of the dry wound dressing. The same applies to the other embodiments of the invention described below.

[0158] In addition to inducing rapid hemostasis, the inventors have also shown that a dried hemostatic polymer composition also temporarily obstructs excess blood flow from a site of heavy bleeding, thereby providing a temporary wound or bleeding site. It has been found to be useful for stabilizing the magnetic field. According to the above embodiment, there is provided a method for temporarily stabilizing bleeding from a wound or bleeding site, which method comprises separately (i) applying a separation matrix (18) to the surface of the wound or bleeding site; (ii) applying an effective amount of a hemostatic agent to the separation matrix to cover the wound or bleeding site, and (iii) separating after the wound or bleeding site is apparently stabilized due to a decrease in blood flow at the site. It is proposed to apply excluding the matrix and hemostatic polymer composition.

The hemostatic agent preferably comprises the novel hemostatic polymer composition of the present invention in dry form,
Other types of compositions can also be used. Similarly, other hemostatic agents can be used as long as they induce hemagglutination at the wound or bleeding site.

The dry hemostatic polymer composition can be applied in a simultaneous fashion well known to those skilled in the art. The hemostatic polymer composition is generally contained in a suitable container, which can include a tube having a proximal end, a distal end, and a lumen extending therethrough for containing the hemostatic polymer composition. The container can also include a syringe adapted to contain the novel hemostatic polymer composition or other container adapted to contain the hemostatic polymer composition, which is applied across the separation matrix to the wound site. Can be used for Other means for temporarily stabilizing the wound or bleeding site in connection with the above embodiments are also contemplated. The dry hemostatic polymer composition of the present invention is contained in a separation matrix (bag). Here the bag acts as a suitable hemostatic sone delivery container. Alternatively, a bandage or other device in which a separation matrix is used to separate the hemostatic polymer composition from the wound or bleeding site can be used.

This type of container employed depends on the choice of prescription means and includes tubes, syringes, applicator guns and the like. The prescription means may be manual or a pump, a fluid compression component, a collapsible container with tubing or a jet or aerosol nebulizer with associated valve mechanism and the like. The preferred formulation means is formulated as a dry powder.

Alternatively, the separation matrix (18) can be attached to the opening of a container containing the hemostatic polymer composition such that the separation matrix separates the hemostatic polymer composition from the wound or bleeding site, thereby allowing the polymer composition to be separated. As long as there is no direct contact between the object and the wound or bleeding site, it can be applied as a single unit to the wound and / or bleeding site.

The separation matrix can be made of the same material as the matrix that is the main component of the hemostatic zone. Indeed, in one embodiment, the separation matrix is applied to the wound site by being applied to the tip of a suitable applicator, such as a syringe. After inducing hemagglutination and hemostasis at the wound site, a separation matrix containing a hemostatic-promoting amount of a hemostatic agent, such as a dry hemostatic polymer composition, is separated from the tip of the container / applicator and the container containing the dry hemostatic agent is removed. It can be left at the wound or bleeding site until a coagulum is formed at the wound site after a long time from the start. The separation matrix, which acts as a dry, detachable hemostatic zone, can then be removed or stripped from the wound site after coagulum has formed at the wound site.

A device for sealing an incision at a wound or bleeding site, including a suitable container containing a hemostatic polymer composition separated at one end by a separation matrix, is also an object of the present invention.

Referring to FIG. 8, a hemostatic polymer composition (20) of the present invention is contained and at its opening comprises a separation matrix (18), wherein the hemostatic polymer composition (hemostatic accelerator (20)) is a syringe ( Shown is a syringe (19) that effectively prevents it from exiting. At the other end, the syringe (19) contains a plunger (21). The method proposes to apply a container containing the hemostatic polymer composition to a wound or bleeding site for a period of time sufficient to temporarily prevent bleeding at the wound or bleeding site.

As soon as the blood comes into contact with the hemostatic polymer of the invention, the bleeding is completely stopped, or
It is believed that it is hindered to the extent that the practitioner is allowed to reapply the device to other bleeding sites or use other hemostatic zones in other wounds or bleeding sites in a similar fashion. The method can be used for a variety of procedures, such as when an emergency technician treats a patient with multiple injuries and some more serious than others. In such cases, the technician / surgeon may find sufficient time to temporarily stabilize the wound and prioritize the preferred treatment order after the wound site has stabilized. Alternatively, the hemostasis zone can be made large enough to cover a large area of multiple bleeding.

Referring to FIGS. 5 (A), (B) and (C), examples of the types of matrices 18-13, 18-14 and 18-15 that can be used to practice the present invention are shown. Be done.

In deciding which form of matrix to use, one needs to refer to: Referring to FIG. 7, a suitable matrix (1
Top and side views of 8) are shown. Microspheres of hemostatic polymer composition matrix
It is recognized that it is larger than the hole (22) in the opening of (18). For example, for HP15, the sphere is
It ranges in size from 40 to 150 microns. Thus, in the above example, the open pores (22) of the matrix (18) are the first dried beads of the hemostatic polymer composition.
It must be smaller than (microsphere). This means that once the beads come into contact with blood at the wound or bleeding site, they swell and become larger than their original dry size of 40-150 microns, which holds them on one side of the separation matrix. This is especially true when considering further assistance. The pore size of the matrix (18) can be obtained by scanning electron microscopy of the fiber cross section. The fiber thickness of the knitted matrix can be the same as the single thickness of the matrix fibers, about 25 microns.

Fibers can be formed as bundles of smaller strands. Matrix fibers are generally made from approximately 15 strands. The individual strands may be irregularly shaped. It is generally preferred that one of the strands be flatter than the other. Many individual strands are about 10 microns wide. Strands as small as 4 microns and as large as 17 microns can be used. The matrix material (23) has a fiber thickness in the range of about 50 to about 55 microns at the intersection of the knitted matrix fibers. Ideally, the separation matrix is less than 50-55 microns thick. Preferably it is about 5 to about 40 microns thick, more preferably it can range in thickness from about 10 to 25 microns.

Particularly preferred composite materials are non-woven in combination with highly absorbent fluid absorbent materials such as polymeric absorbent fibers or particles selected from the group consisting of modified starch and high molecular weight acrylic polymers having hydroxyl groups. It is a matrix. Preferably, the separation matrix is made of silk.

The inventor has also found that the hemostatic polymer composition of the present invention clears wounds prior to accelerating blood aggregation and clot formation at the wound or bleeding site. This is important considering that recently the amount of water retained in equilibrium with injured skin or cuts, burns and abrasions has been shown to dramatically alter wound healing. It is a discovery. It is believed that the molecules of the hemostatic polymer composition are reactive with the local environment of the wound or bleeding site surface, thereby allowing excess fluid, bacteria and wound exudate to be aspirated from the environment prior to inducing clot formation.

An improved fibrin glue marketed in Europe is Usis Thrombin,
Biodegradable collagen patch impregnated with aprotinin and human fibrinogen
(TAF patch). An example of a TAF patch is Hafslund Nycomed in Europe
TachoComb® patch marketed by Parma, DE. The patch also contains calcium chloride which enhances aggregation. In use, the patch is removed from the package, dipped in saline solution and applied to the bleeding organ with light pressure for at least 5 minutes. Once the bleeding has stopped, the patch is left in place by the surgeon and the cavity closed.

A major drawback of the use of fibrin glue and TAF patches is that they both contain human fibrinogen, a protein purified from human blood. Due to the high risk of HIV and hepatitis virus infection, the Food and Drug Administration abolished the use of human fibrinogen in 1978 in the United States.

Accordingly, one embodiment of the present invention provides an effective hemostatic patch comprising a matrix and a hemostatic polymer composition.

This example provides a hemostatic patch suitable for rapidly stopping bleeding and inducing rapid clot formation at a wound or bleeding site. The patch comprises a dry, sterile, storage-stable, flexible matrix that includes a hemostatic polymer composition on only one side that provides a dry hemostatic zone. The patch is very effective at accelerating blood clumping and clot formation at the interface between the wound or bleeding site surface and the patch's reagent zone.

Referring to FIG. 6b, a patch including a flexible adhesive substrate (17) and a hemostatic zone (12)
(17a) is shown. The patch can be applied externally to the wound or bleeding site, just like a band-aid or dressing, to stop bleeding at the wound or bleeding site and accelerate clot formation. Alternatively, the patch can be used to hermetically seal body tissue. Consider air leakage from wounds in the lungs. An efficient way to occlude or stop the wound or bleeding site is to apply the patch to the wound or bleeding surface, for example by holding it under light pressure, for a suitable period of time to induce hemostasis as described above. . During this time, in addition to hemostasis, a hermetic seal is formed. Similar things
This applies to dry wound dressings that include a hemostatic zone or wound dressings that include a hemostatic zone carried on a substrate.

Unlike conventional patches, the patches proposed in the present invention do not require exogenous human proteins such as fibrinogen as a component, which can prevent the introduction of dangerous contaminating viruses.

Bleeding of soft organs such as the spleen, liver, lungs or pancreas resulting from trauma or surgery is generally very difficult to treat. Soft organs are difficult to tie because the tissue can be easily torn, granulated or tattered. As a result, surgeons often resort to the use of electrocautery resulting in further destruction of the patient's tissue. Thus, any bandage, dressing or patch containing the hemostatic polymer of the present invention can be used in stopping bleeding from injuries on soft organs. Therefore, any of the preferred wound dressings are highly effective in stopping bleeding from problematic soft organs. In addition, the flexible matrix containing the hemostatic polymer composition (hemostatic zone) can be easily used and easily shaped to the contours of the body.

Other uses of hemostatic patches include topical treatments such as burns or tissue transplants. Patches of the invention intended for topical use preferably include additives such as anti-infective drugs. Bactericides, fungicides and wound healing agents can also be added. Neomycin and bacitracin are examples of specific additives in patches intended for topical use, in addition to the other therapeutic agents referenced above.

Another important advantage of the present invention is its flexibility. That is, the patch easily conforms to the contours of the organ or body surface, making the operation of applying the patch faster. As a result, there is less overall blood loss to the patient and less time is required for surgery.

The patch can also be used in field settings, such as when an emergency technician encounters a patient with multiple wounds. Here, the patch or any other embodiment of the invention can be applied to multiple wound sites to effectively stop bleeding at the wound or bleeding site.

Like other wound dressings, the hemostatic patches of the present invention that include a hemostatic polymer composition are also useful for treating animals, preferably humans and other mammals. Thus, any of the companion animals, livestock and wild animals can be treated with any of the embodiments of the present invention.

The various wound dressings contemplated by the present invention can be made to fit a particular shape and size, generally corresponding to their intended use.

The hemostatic zone can also be spherical, conical, cubic or conical, and can be pre-fabricated into small prisms, such as those for filling body cavities. Such an embodiment can be used in a dental patch used to stop bleeding of a dental cavity due to tooth extraction or other forms of dental trauma.

Patches that include a hemostatic zone can be designed to facilitate application for anastomosis or fusion of the ends of surgically or otherwise severed blood vessels or other body lumens. A patch or other suitable wound dressing that includes a hemostatic zone can be used in connection with a graft used to fuse the ends of blood vessels or other lumens.

First aid bandages are routinely applied to any cuts, abrasions, pits, roughness, etc. on the skin, and are placed over the wound, usually with a flexible adhesive backing material. Used in conjunction with antimicrobial ointments applied to retained absorbent gauze pads.

The well-known and common Band-Aid (a trademark of Johnson & Johnson) and Curad (
Over the years since the introduction of the Kendall Corporation trademark, improvements have been made in two basic areas: bandage materials and bandage packaging.
The development of materials used in bandages has generally improved the absorbency and easy release of wound areas from gauze pads and the vapor permeability and hydrophobic performance of backing materials. The development of packaging has provided a variety of designs that maintain sterility during storage and allow the user to easily open and apply the bandage without having to touch an adhesive backing or absorbent gauze pad.

There are currently two main types of bandages: three sizes of versatile rectangular adhesive strips with a centrally located rectangular absorbent gauze pad, and a variety of specially shaped bandages (round). Dotted, square, "H" shaped and "bow tie" shaped adhesive bandages) with similarly centrally located absorbent gauze pad. Conventional adhesive wound dressings typically include an adhesive coated sheet with a removable protector over the adhesive coating. Application of these wound dressings to a patient can be accomplished by removing the protector from the adhesive sheet and allowing the sheet to adhere to the skin at the wound site of the patient.

According to the above, a wound dressing bandage is provided. 6A, (i) central portion-reagent zone (14) adapted for direct application to the wound or bleeding site;
And (ii) a strip (16) for attachment to an area in continuous and spaced relation to the wound or bleeding site, whereby the bandage is substantially contoured or flexible. A central portion of the bandage at the interface of the wound or bleeding site surface with the central portion of the bandage, the strip including a strip adapted to be applied without wrinkling to the portion and adapted to securely attach. A bandage (16a) comprising a hemostatic zone comprising a suitable matrix having a hemostatic promoting amount of a hemostatic polymer composition effective to accelerate blood aggregation and clot formation is shown.

Topical treatment of body tissues, diseases and wounds requires that certain drug components be maintained at the treatment site for an effective period of time. Topical treatment of wet mucosal tissues has been difficult when natural body fluids tend to rapidly wash away topically applied drug compositions. In the oral cavity, saliva, replacement of natural mucosal tissue, and eating, drinking, and talking movements are typical of the problems that have limited the effectiveness and residence time of drug carriers.

Denture adhesive paste is a well known bioadhesive product. However, although drugs such as local anesthetics may be used in the paste to relieve gum pain, these formulations provide protection of the scab or bleeding site in oral tissues or local delivery of therapeutic agents, rather than Originally, it is used because of their adhesive properties for adhering dentures to the gums. U.S. Pat.Nos. 4,894,232 and 4,518,721
A denture adhesive tape is disclosed. Thus, one embodiment of the present invention relates to an adhesive paste adapted for use in controlling or promoting coagulum formation in the oral cavity.

Bandages or bioadhesive laminate films that are thin and flexible, and therefore have a reduced foreign body sensation, are also well known. For example, U.S. Pat. Nos. 3,996,934 and 4
, 286,592. These products are used to deliver drugs through the skin or mucous membranes. Laminate films are usually adhesive layers, reservoirs.
) Layer, and a backing layer. Thus, at least one embodiment of the present invention relates to a bandage or bioadhesive laminate film that can be used to seal a bleeding or wound site.

Bioadhesive gels used for application to mucosal tissues and especially the oral cavity are also contemplated by the present invention. Such gels can be adapted to include the novel hemostatic polymer compositions of the present invention for use in inducing blood aggregation in mucosal tissue. For example, US Pat. No. 5,192,802 discloses a bioadhesive dental gel made from a mixture of carboxymethyl cellulose and xanthan gum. Bioadhesive gels are also described in U.S. Pat.Nos. 5,314,915, 5,298,258 and 5,642,749.
No. The gels disclosed in these patents use aqueous or oily media and different types of bioadhesives and gelling agents. All of the above cited patents are incorporated herein by reference in their entirety.

In addition, film delivery systems for use on mucosal surfaces are also known. These types of systems, which are water insoluble and are usually laminated, extruded or in the form of composite films, are disclosed in U.S. Pat.Nos. 4,517,173, 4,572,832, 4,713,24.
3, No. 4,900,554 and No. 5,137,729, each of which is incorporated herein by reference. Accordingly, the present invention also provides a drug carrier for application to mucosal surfaces to provide rapid blood aggregation and therapeutic drug delivery to the site of application, surrounding tissues and other body fluids with an effective residence time. Provide a device.

Another embodiment of the present invention is directed to a suture coated with the hemostatic polymer composition of the present invention. Such sutures can be used after surgery, where they can be used to prevent or minimize postoperative bleeding that occurs in some postoperative traumas.

Another embodiment of the present invention contemplates a suitable container for delivering the dry hemostatic polymer composition of the present invention to a wound or bleeding site. A preferred device for delivering a hemostatic polymer composition that acts as a hemostatic zone is shown in FIG. Shown here is an applicator gun (25) comprising the hemostatic polymer composition (20) of the present invention. The hemostatic polymer composition of the present invention can be used to apply to a wound or bleeding site,
Various types of spray tips (26) (ac) are also shown.

Another embodiment of the present invention contemplates a means for administering the hemostatic zone (12) of the present invention, eg, to an artery or vein. Shown in FIG. 10 is a forceps (24) by which a dry hemostatic zone (12) separated by a separation matrix (18) is occluded to an artery or vein and blood clots and It can be effectively used to accelerate coagulum formation. Alternatively, similar devices can be used to temporarily stabilize multiple wounds.

The invention will be described in detail with reference to the following examples. The preferred embodiment is
It is understood that it is not intended to limit the scope of the invention claimed herein.

[0199]

Example 1 Activation and concentration of platelets and plasma proteins with hemostatic agents Dry spheres or beads were prepared with cross-linked dextran (MW 65,000-70,000) and epiclohydrin. The obtained cross-linked dextran has exclusion limits depending on the degree of cross-linking.
It had between 100,000MW and 300,000MW. 10 ml of porcine blood was drawn and placed in 0.1055M buffered sodium citrate. 0.3 ml of citrated blood was added to 0.05 ml of 100,000 MW, 300,000 MW and 650,000 MW cross-linked dextran in a Petri dish. Platelet and plasma protein enrichments were observed by phase contrast microscopy at 200X and 400X. Within 1 minute, platelets began to aggregate around the sphere. A layer of concentrated fibrinogen (fibers or strands) was observed within 2 minutes. Within 2 to 5 minutes,
A tight fibrin clot, consisting of aggregated platelets, erythrocytes and stable fibrin, was formed surrounding the dextran spheres. Example 2 Reduction of Coagulation Time by Hemostatic Agent Dry spheres or beads were prepared with cross-linked dextran (MW65,000-70,000) and epiclohydrin. The resulting cross-linked dextran had an exclusion limit of 300,000 MW. 10 ml of sheep blood was collected. 1.5 ml of sheep blood was placed in 5 tubes. Test tube # 1 served as a control containing only citrated sheep blood. Wet cross-linked dextran (.01 g + 0.5 ml saline) was added to tube # 2. Wet cross-linking dextran (
0.01 g + 1.0 ml saline) was added to tube # 3. Dry cross-linked dextran (.01g) was added to tube # 4. Dry Pharmacia Dextran T70 (.01 g, uncrosslinked) was placed in test tube # 5. Coagulation tests were performed at 39 ° C (normal sheep body temperature). The obtained clotting times are as follows: Test tube # 1 = 14 minutes; Test tube # 2 = 5 minutes; Test tube # 3 = 5 minutes; Test tube # 4 = 9.5 minutes; Test tube # 5 = 14 Minutes. These results show that cross-linked dextran (0.01 g) activates platelets and coagulation factors and reduces coagulation time by 64%. Example 3 Hemostatic effect of cross-linked dextran on splenic incision This example shows the effect of cross-linked hemostatic agent on surgical incision of the spleen. The abdomen of the pig was surgically opened to expose the spleen. A surgical incision 6 cm long and 2 cm deep was made in the spleen. Bleeding was controlled by compression. 2 g of dry cross-linked dextran (300,000 MW
The exclusion limit) was placed in the incision. Hemostasis was achieved by continuing compression for 5 minutes. 15
Hemostasis of the splenotomy was maintained when the cross-linked dextran / coagulum was removed with forceps after a minute. Example 4 Hemostatic effect of cross-linked dextran on liver trauma This example shows the effect of cross-linked hemostatic agents on experimentally induced liver trauma. A midline incision was made in the abdomen of the pig to expose the liver. In the liver, length 10
A surgical incision, 3 cm deep, was made. Excessive bleeding was controlled by compression. 4 g of cross-linked dextran (300,000 MW exclusion limit) was placed in the injured liver. The compression was continued for 5 minutes until hemostasis was obtained. Hemostasis of the liver incision was maintained when the cross-linked dextran / coagulum was removed with forceps after 15 minutes. Twelve arteries and veins were cut and sealed with cross-linked dextran / coagulum. Example 5 Hemostatic properties of cross-linked dextran hemostatic agent in arterial perforation A 100 lb pig was anesthetized and heparinized (400 units / kg). An incision was made to expose the femoral artery. French catheter # 9 was inserted into the artery through a perforation through the artery wall. A 1 ml syringe (cut to fit the curved surface of the artery) containing 0.2 ml of dry cross-linked dextran (300,000 MW exclusive) was placed over the injured artery and catheter. Blood entered the syringe by slowly removing the catheter from the puncture site while pushing the hemostat into the artery. The blood began to clot as the leaked blood came into contact with the hemostatic agent. The syringe was placed arterially, but pressure was applied to the femoral artery to ensure that blood flow through the artery was not blocked. The syringe was slowly removed after 5 minutes. The arterial perforation site was sealed and hemostasis was maintained for 1 hour of observation. Blood flow through the femoral artery was maintained throughout the sealing procedure.

A control arterial perforation was created in the symmetrical femoral artery of the same heparinized pig. The femoral artery was exposed and cleaned. A # 9 French catheter was inserted into the artery through a perforation through the artery wall. Tensile pressure was applied to the fascia and skin over the catheter and perforation site. The catheter was withdrawn while maintaining pressure. Bleeding was controlled solely by pressure at the perforation site, resulting in cessation of blood flow through the femoral artery. The pressure was maintained for 10 minutes and then released, but the perforation site of the artery began to bleed heavily. The bleeding perforation site was sealed with the dry cross-linked dextran described above. Example 6 A 100 lb pig was anesthetized and heparinized (400 units / kg). The purpose of this experiment is to test the effectiveness of the hemostatic polymer composition (HP15) as a hemostatic agent in an animal (pig) model with a coagulation system similar to humans. The abdomen of the pig was surgically opened to expose the spleen and liver. A 6 cm long and 2 cm deep surgical incision was made in the spleen.
Heavy bleeding was controlled by compression. 2g of dry HP15 was placed in the incision. A spatula was used to apply HP15. The spleen was pressed together for 5 minutes.

Complete hemostasis was achieved within 5 minutes. After 15-20 minutes, HP15 was removed with forceps. Hemostasis was maintained, but bleeding can be induced by cutting live tissue next to the wound. Dry HP15 was very effective in achieving and maintaining hemostasis at the site of heavy bleeding in the spleen.

In conclusion, the hemostatic polymer composition of the present invention and other similar cross-linked polysaccharides etc. are very useful in stopping bleeding and accelerating clot formation at the site of a wound or bleeding.

A second surgical incision (10 cm x 3 cm deep) was made in the pig liver. Again, there was heavy bleeding, which was controlled with a 4X4 gauze dressing compress. 4g HP15 (4gms
) Was applied to a bleeding traumatic liver. The compression was applied for 5 minutes. At the end of 5 minutes, hemostasis was achieved. The wound containing HP15 was observed for 1 hour, and it was confirmed that hemostasis was complete. A second wound (10 cm x 3 cm deep) was made in the second hole in the liver. HP15 (4g
) Was applied and hemostasis was achieved in 5 minutes. After 15 minutes, the coagulated HP15 was removed with forceps, and hemostasis of the liver incision was maintained. The living tissue on both sides of the coagulated wound remained well perfused and bleeded heavily when cut. All coagulated G-100 was removed and hemostasis was maintained. When the severed artery was exposed, it would bleed if all coagulated HP15 was removed and the artery was opened. Twelve arteries and veins were cut and sealed with HP15. The cut and sealed vessels were of various sizes. The artery spanned 2 mm to 5 mm. Veins ranged from 2 mm to 10 mm. Pictures (slides) were taken of: Incision, heavy bleeding, HP15 applied. HP15 coagulation, sealed wounds, HP15 removal (with cross section) and sealed blood vessels. HP15 was very effective in rapidly achieving hemostasis in liver and spleen trauma. The polymer composition of the present invention is
It appeared to be biocompatible. Example 7 The purpose of this experiment was the conventional Avitene, Cochrum Fibrin Glue (Patent No. 5,510,1).
No. 02) and the dry hemostatic polymer composition of the present invention. 4 cm ×
Two 2 cm liver incisions were sealed with Avitene (very bad results). Two liver incisions were sealed with Cochrum Fibrin Glue (Patent No. 5,510,102). Cochrum Fibrin Glu
Although e attached the incision better than Avitene, this fibrin glue (plasma / polymer) was unable to maintain hemostasis in heavily bleeding (arterial bleeding) wounds. The Fibrin Glue tended to stop bleeding (due to concentrated fibrinogen and bovine thrombin) but could not maintain hemostasis under arterial pressure.

Upon application of the hemostatic polymer composition of the present invention, rapid aggregation of blood was observed at the incision site. Duration was shorter than that required in Cochrum Fibrin Glue and Avitene. Hemostasis was maintained unlike Fibrin Glue and Avitene. Example 8 Thigh Access (using the "Anesthesia Protocol for Pigs" below) and Hemostasis Zone ("HZ") Test Procedure Pigs were anesthetized and heparinized (400 units / kg). An incision was made to expose the femoral artery. French catheter # 8 or # 9 was inserted into the artery through a perforation through the artery wall. A syringe (cut to fit the curved surface of the artery) containing dry cross-linked dextran (limited to 300,000 MW) was placed over the injured artery and catheter. Blood entered the syringe by slowly removing the catheter from the puncture site while pushing the dry hemostatic zone into the artery. As the leaked blood came into contact with the hemostatic agent contained in and around the reagent zone, the blood began to clot. The syringe or FIG. 8 was held in place using gentle hand pressure. After 5 minutes, the syringe was slowly removed. From 5 minutes to 10 minutes, at intervals of 5 minutes, 6 minutes, 7 minutes ...
At 10 minutes, the arterial perforation site was continuously checked. At each minute interval after 5 minutes, the arterial perforation site was visually observed to observe continuous coagulation. The pressure was then released and the surrounding area was observed for continued bleeding around the hemostasis zone or around the tip of the syringe. If no bleeding was observed, the syringe was gently removed from the wound site. Remaining on the wound site was a separation matrix that had the hemostatic polymer composition of the present invention dispersed therein and served as a hemostatic zone. It was later scraped or gently pulled.

The protocol for the above experiments is reproduced below. The experiment demonstrates the successful application of a removable wound dressing, which acts as a dry detachable hemostatic zone and is then removed after inducing blood clumping and clot formation at the wound or bleeding site.

In the above example, the tip of the syringe containing a separating matrix that separates the dry hemostatic polymer composition from direct contact with the wound surface serves as a dry hemostatic zone.
Dispersed in the matrix herein are molecules of the hemostatic polymer composition that act as a dry hemostatic zone in association with the separation matrix. Protocol for the above experiment The animal is placed in the supine position and the posterior right leg is bent toward the tail. Shave the surgical access site. The femoral artery is approached with a longitudinal incision over the femoral branch of the sartorius and gracilis. The muscle tissue is divided and the segment of the femoral artery located below the end of the gracilis muscle is isolated. The femoral artery is loosely wrapped with a suture to isolate the vessel and facilitate manipulation. Stop the flow by pulling with a suture. Make a small incision 1-2 mm with iris scissors enough to penetrate the artery wall (arteriotomy). Introduce an 8 or 9 French catheter into the arterial lumen through the arteriotomy, ensure it is open, release the suture, remove the catheter, and create the bleeding wound site. As the catheter is withdrawn, a syringe carrying the HZ (see Figure 8) is placed over the wound site. Position the syringe using gentle hand pressure. After 5 minutes, check the parts at minute intervals (5, 6, 7, 8, 9, ... 10 minutes). (At each of these times, coagulation was observed.) Release manual pressure. Observe for continuous bleeding around the circumference of the HZ (tip area of the syringe). If not, gently remove the syringe from the wound site and leave the HZ at the wound site.
Later, the HZ can be removed by "scraping" it from the wound site or by gently stripping it from one end to the other. Anesthesia protocol-Pig weight: 25 to 90 kg Pretreatment: Atropine 0.5 mg / 10 kg (not to exceed 1.5 mg) IM Acepromazine 1 mg / 10 kg (not to exceed 5.0 mg) IM Induced anesthesia: Ketamine HCl I 5 mg / kg IM (as needed) Repeatable 6 times) Xylazine 20-80 mg IM, in pigs over 40 kg. Introduced an isoflurane 3.5% mask. Maintenance anesthesia: Isoflurane (usually 2.0% -3.0%) through the endotracheal tube. Anticoagulant (if required) Heparin 300 units / kg body weight first. ACT is measured every 30 minutes and heparin is repeatedly given as needed. 150 units / kg at intervals of 30 minutes. Keep ACT above 400. Recovery: Keep warm and comfortable on chest (on sternum). Butorphanol 0.1-0.3 mg / kg IM every 4 hours if needed. Antibiotics as directed by the veterinarian. Measures: Indoor for short-term management. For long-term management, leave it outdoors. Fluid: A normal saline solution through the ear vein (or middle metacarpal vein or metatarsal vein). Moderate infusion, usually 500-1000 cc per procedure or as needed, especially for cardiac catheter procedures Euthanasia: Under anesthesia, give a rapid IV injection of 10-20 cc concentrated (2 mEq / ml) KCl. Example 9 The abdominal access (using the "anesthesia protocol" for pigs below) procedure and the hemostatic zone ("sack") of the test animals are placed in the supine position. Shave the abdominal area for surgical access. A midline abdominal incision from the xiphoid process to the pubis exposes the abdominal cavity. A Balfour retractor is placed to facilitate access to the liver, spleen and descending aorta. Wet gauze and surgical towels should be used to protect the abdominal organs and tissues. Using a No. 20 scalpel blade, make an incision approximately 7-9 cm long and 1.5-2 cm deep. Make sure the area is free to shed blood. Aspirate the site with gauze and immediately place the bag on the site. Hold the bag in place with gentle hand pressure. After 5 minutes, check the parts at minute intervals (5, 6, 7, 8, 9, ... 10 minutes). (At each of these times, coagulation was observed.) Release manual pressure. Observe for continuous bleeding around the perimeter of the bag. If not, remove the bag by gently “scraping” it from the wound site or by gently scraping it from one end to the other. Anesthesia protocol-Pig weight: 25 to 90 kg Pretreatment: Atropine 0.5 mg / 10 kg (not to exceed 1.5 mg) IM Acepromazine 1 mg / 10 kg (not to exceed 5.0 mg) IM Induced anesthesia: Ketamine HCl I 5 mg / kg IM (as needed) Repeatable 6 times) Xylazine 20-80 mg IM, in pigs over 40 kg. Introduced an isoflurane 3.5% mask. Maintenance anesthesia: Isoflurane (usually 2.0% -3.0%) through the endotracheal tube. Anticoagulant (if needed): First 300 units of heparin / kg body weight. ACT is measured every 30 minutes and heparin is repeatedly given as needed. 150 units / kg at intervals of 30 minutes. Keep ACT above 400. Recovery: Keep your chest warm and comfortable. Butorphanol 0.1 to 0 every 4 hours if needed.
3 mg / kg IM. Antibiotics as directed by the veterinarian. Measures: Indoor for short-term management. For long-term management, leave it outdoors. Fluid: A normal saline solution through the ear vein (or middle metacarpal vein or metatarsal vein). Moderate infusion, usually 500-1000 cc per procedure or as needed, especially for cardiac catheter procedures Euthanasia: Under anesthesia, give a rapid IV injection of 10-20 cc concentrated (2 mEq / ml) KCl. Example 10 This experiment shows the effect of using a hemostatic zone in inducing hemagglutination at a wound or bleeding site. The reagent zone here comprises a matrix comprising the novel dry hemostatic polymer composition of the present invention together with added thrombin. The dry bead size spheres of the composition were 10 to 120 microns. Thrombin: Dry lyophilized Usis Thrombin (appearance of dried flakes). The dried thrombin was used at 500 units per 0.5 g of the hemostatic polymer composition of the present invention. Thrombin US Pharmacopeia Parke-Davis 5000 units / vial.

The procedure is similar to Example 9 except the hemostatic agent comprises exogenously added thrombin. Similar experiments with the hemostatic polymer composition of the present invention in connection with bovine collagen gave similar results when used to seal porcine femoral arteries. Here, 0.01 ml abitene was added to prevent the polymer composition from falling out of the syringe.
Used with 0.2 ml of polymer composition. Bovine collagen was used as the separation matrix.

Dry Thrombin with Hemex-1 part thrombin poured into 10 parts Hemex in vitro. The test tube was subsequently stirred (shaken) for 30-60 seconds. Hemostasis zone of mixture (HZ)
I put it in a bag. The abdominal access (using the "anesthesia protocol" for pigs below) procedure and hemostasis zone ("sack") test animals are placed in the supine position. Shave the abdominal area for surgical access. A midline abdominal incision from the xiphoid process to the pubis exposes the abdominal cavity. A Balfour retractor is placed to facilitate access to the liver, spleen and descending aorta. Wet gauze and surgical towels should be used to protect the abdominal organs and tissues. Using a No. 20 scalpel blade, make an incision approximately 7-9 cm long and 1.5-2 cm deep. Make sure the area is free to shed blood. Aspirate the site with gauze and immediately place the bag on the site. Hold the bag in place with gentle hand pressure. After 5 minutes, check the parts at minute intervals (5, 6, 7, 8, 9, ... 10 minutes). (At each of these times, coagulation was observed.) Release manual pressure. Observe for continuous bleeding around the perimeter of the reagent zone (bag). If not, remove the bag by gently “scraping” it from the wound site or by gently scraping it from one end to the other. The HZ is separated from the wound site after this procedure. Example 11 The following example illustrates the use of the novel hemostatic polymer composition of the present invention in humans, ie, the application of the hemostatic polymer composition (ie HP15) to the control of bleeding. A subject having a cut on the tip of the middle finger was observed. The incision was measured to be about 8 to 9 mm long and was bleeding heavily. The wound was allowed to bleed freely for several minutes and if the bleeding did not stop, a small amount of hemostatic polymer composition (dry HP15) was applied to the bleeding surface of the wound. A small bandage was applied over the wound and the polymer composition. It was observed that the bleeding stopped immediately. After about 20 to 45 minutes, the bandage was removed from the wound site and the wound was observed. It was found that the wound was covered by blood-polymer coagulum. The coagulum was observed to adhere well to the surrounding skin. It was observed that the polymer composition was saturated with blood which had aggregated to form a flexible coagulum, which protected the wound. The resulting coagulum material was somewhat resistant to removal and was washed away under running hot water. Importantly, the wound did not bleed again when the coagulum material was removed. A clean bandage was applied to the wound and healed without incident. It was observed that the properties of the coagulum were very similar to those observed with pig blood. Example 12 This experiment demonstrates the biocompatibility of HP15 and HP20 (crosslinked polysaccharide) in skin incisions in a sheep model.

[0209]   Four skin incisions (# 1- # 4) were made in and around the left flank of anesthetized sheep.

Incisions 1 and 2 were treated with a hemostatic-promoting amount of HP15 to stop bleeding. Incision 3
Incision # 4 was treated untreated (control) with a similar amount of HP20. Since the sheep are very active when conscious and awake, two sutures (5-0 Dermalon) were used to prevent the skin from opening.

[0211]   Note: 1 incision had a 1 cm hematoma created by a 5-0 Dermalon cut needle.

HP15 and Hp20 were observed to be very effective hemostatic agents in sealing skin incisions. Subsequently, histological sections of sheep skin treated with the above agents were studied to confirm the following. Incisions # 1 (HP15) and # 2 (HP20) were completely healed on histological sections. However, HP15 remained in the tissue and the spheres were observed to be biodegraded and surrounded by tiny mononuclear cells. There was no indication of host reaction to HP15.

Incision # 3 (HP20 treatment) showed identical results to HP15 treated wounds. That is, the histological examination revealed similar tissues. However, HP20 was observed to be more biodegradable than HP15. Also, like HP15, HP20 was very biocompatible and the sections did not show any host response to it.

[Brief description of drawings]

1 and 1a are schematic diagrams of the hemostatic reaction. This figure shows the various reactions that occur between the cross-linked polymer and the platelets at the site of the wound or bleed, which is a characteristic feature of hemostatic polymer compositions.

FIG. 2 shows surface reactions that occur when a hemostatic polymer composition contacts a wound or bleeding site and activates the aggregation cascade.

FIG. 3 shows the aggregation pathway that occurs during the rapid aggregation of hemostatic polymer compositions when applied to a wound or bleeding site.

[Figure 4]   FIG. 4 shows an embodiment of the invention relating to a plan and side view of a hemostatic zone.

FIG. 5 shows an expanded view of the different matrix textures and materials used in the practice of the invention.

FIG. 6 shows another preferred embodiment of the present invention for a bandage with a central portion including a hemostatic zone attached to one side of a substrate. FIG. 6 (A) shows another embodiment showing a hemostatic patch having a hemostatic zone.

[Figure 7]   FIG. 7 shows a plan view and a side view of the matrix separation matrix.

[Figure 8]   FIG. 8 shows a syringe-like device for applying the hemostatic polymer composition of the present invention.

FIG. 9 illustrates yet another embodiment of the present invention, showing a commonly available applicator gun for applying a hemostasis promoting agent (hemostatic polymer composition of the present invention).

FIG. 10 illustrates the use of forceps to place a hemostatic zone over a wound or bleeding site.

FIG. 11 shows activation of platelets by ionic concentration of fibrinogen on the surface of the hemostatic polymer composition.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 7/04 A61L 25/00 K 17/02 A C08G 59/04 15/03 (81) Designated country EP ( AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM , AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, Z, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK , LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, T M, TR, TT, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Gunther, Robert, A. California 95616, Davis, Chesapeake Bay Avenue 3117 (72) Inventor Gem Trad, Susan, A. California 95616, San Francisco, Fairmount Street 191 (72) Inventor Benin Sig, Franklin, M Calif United States of America Lunia 95814, Sacramento, Capital Mall 400, Elevens Floor F Term (reference) 4C081 AA01 AA07 AA08 AA12 AA14 AC06 BA11 BA16 CA051 CC03 CD121 CD31 CE01 CE02 CE03 DA12 EA05 EA13 4A08 MAA27 MA56 MA13 MA13 MA13 ZA531 ZA532 ZA891 ZA892 4C086 AA02 AA03 FA02 MA03 MA05 MA13 MA27 MA56 MA63 NA14 ZA53 ZA89 4J036 AE07 DB02 FA14 JA15

Claims (67)

[Claims] 1. A dry, releasable, storage-stable, sterile wound dressing that provides a dry hemostatic zone for blood coagulation and clot formation at the interface of the wound surface and said hemostatic zone. A wound dressing comprising a matrix containing an accelerating hemostatic-promoting amount of a hemostatic agent. 2. The hemostatic agent comprises a dry hemostatic polymer composition comprising a reaction product of an uncharged substance containing an organic hydroxyl group and a bifunctional substance containing at least one of a halogen atom or an epoxy group. The wound dressing of claim 1, wherein a functional material is reactive with the organic hydroxyl groups of the uncharged material. 3. A dry, comprising substrate and wound dressing according to claim 1.
Sterile, detachable wound dressing. 4. The wound dressing according to claim 1, wherein the substance containing an uncharged hydroxyl group is a carbohydrate, a polysaccharide or a polyol. 5. The wound dressing of claim 1, wherein the carbohydrate is sucrose or sorbitol. 6. The wound dressing according to claim 4, wherein the polysaccharide is dextran, starch, alginate or cellulose. 7. The wound dressing according to claim 6, wherein the polysaccharide is dextran. 8. The wound dressing of claim 1, wherein the polyol is polyvinyl alcohol. 9. The wound dressing according to claim 1, wherein the substance containing a halogen atom is epichlorohydrin or dichlorohydrin. 10. The wound dressing according to claim 1, wherein the substance containing an epoxy group is diepoxybutane, diepoxypropyl ether or ethylene-glyco-bis-epoxypropyl ether. 11. The wound dressing of claim 1, wherein the hemostatic polymer composition further comprises at least one of collagen, fibrinogen and thrombin. 12. The wound dressing of claim 1, further comprising a drug. 13. The drug is an anti-inflammatory analgesic, a steroid anti-inflammatory drug, an antihistamine, a local anesthetic, a bactericidal or disinfectant, a vasoconstrictor, a chemotherapeutic drug, an antibiotic, a keratolytic agent, a corrosive agent, an antivirus. 13. The wound dressing of claim 12, which is at least one of a drug and a mixture thereof. 14. A method for stopping bleeding and inducing rapid blood coagulation and clot formation at a bleeding or wound site, comprising the dry wound dressing of claim 1 at the wound or bleeding site. A method comprising applying for a period of time sufficient to induce rapid blood coagulation and removing the wound dressing after blood has clotted at the bleeding or wound site. 15. The dry wound dressing is obtained by pressing the hemostatic agent-containing surface of the dry wound dressing against the surface of the wound or bleeding site for a period until coagulation occurs at the interface between the hemostatic surface and the surface of the wound or bleeding site. 15. The method of claim 14 including applying. 16. Applying the dry wound dressing by using forceps or a pressure controlled syringe to accelerate blood coagulation and clot formation at the interface between the wound or bleeding site surface and the dry hemostatic zone of the dry wound dressing. 15. The method of claim 14, comprising: 17. The method of claim 14, comprising inducing hemagglutination for a period of between 4 minutes and 20 minutes. 18. The method of claim 17, comprising inducing hemagglutination wherein the period of time is in the range of 6 to about 10 minutes. 19. The method of claim 14, comprising inducing hemagglutination and hemostasis by a dry hemostatic zone of a dry wound dressing. 20. The method of claim 14, which comprises inducing hemagglutination and hemostasis by contacting the polymer composition contained in the reagent zone with blood or bleeding tissue without the addition of exogenous thrombin. 21. Attracting and activating platelets and coagulation factors normally found in blood at the wound and hemostatic zone surfaces by a hemostatic polymer composition contained in the hemostatic zone of a dry wound dressing. the method of. 22. The method of claim 14, comprising concentrating blood fibrinogen within the bleeding site with the hemostatic polymer composition. 23. The method of claim 22, wherein the concentrated fibrinogen attracts and activates platelets and coagulation factors found in blood within the bleeding site. 24. A dry, sterile wound dressing that provides an antimicrobial hemostatic zone effective to accelerate blood aggregation and clot formation at the interface between the wound or bleeding site surface and the reagent zone. A dressing comprising a matrix comprising a complex comprising a hemostatic promoting amount of a hemostatic agent and an effective amount of an antimicrobial agent. 25. The hemostatic agent comprises a dry hemostatic polymer composition comprising a reaction product of an uncharged substance containing an organic hydroxyl group and a bifunctional substance containing at least one of a halogen atom or an epoxy group. 25. The wound dressing of claim 24, wherein a functional material is reactive with the organic hydroxyl groups of the uncharged material. 26. A hemostatic composition suitable for rapidly stopping bleeding and inducing rapid clot formation at a wound or bleeding site, which provides a dry hemostatic zone on only one side. A patch containing a flexible matrix suitable for dry and aseptic storage, which is effective for accelerating blood aggregation and clot formation at the interface between the wound or bleeding site surface and the reagent zone of the patch. There is a patch. 27. The hemostatic agent comprises a dry hemostatic polymer composition comprising a reaction product of an uncharged substance containing an organic hydroxyl group and a bifunctional substance containing at least one of a halogen atom or an epoxy group. 27. The hemostatic patch of claim 26, wherein the functional material is reactive with the organic hydroxyl groups of the uncharged material. 28. The hemostatic patch of claim 26 in a form useful in stopping bleeding from injury to a parenchymal organ. 29. The hemostatic patch of claim 26, wherein the matrix is biodegradable. 30. The hemostatic patch according to claim 29, wherein the biodegradable matrix is selected from the group consisting of absorbable gelatin, calcium alginate, calcium / sodium alginate, collagen and oxidized regenerated cellulose. 31. The hemostatic patch according to claim 30, wherein the biodegradable matrix is absorbable gelatin. 32. A sterile package comprising an outer protective layer and the hemostatic patch of claim 26. 33. A method of stopping bleeding from a wound comprising applying the hemostatic patch of claim 26 to the wound surface of the wound for a period of time sufficient to stop bleeding. 34. A method for accelerating rapid blood coagulation and clot formation at a bleeding or wound site, which comprises the time period for coagulation to occur at the interface of the hemostatic patch and the wound or bleeding site, on the wound or bleeding surface. 27. Applying a hemostatic agent-containing surface of the patch of claim 26, and removing the hemostatic patch after a coagulum has formed at the wound or bleeding site. 35. The method of claim 34, wherein the period of time is about 4 to about 20 minutes. 36. Applying the dry wound dressing by pressing the hemostatic agent-containing surface of the hemostatic patch against the damaged surface for a period of time until coagulation occurs at the interface of the hemostatic patch and the damaged surface. The method described. 37. A bandage, comprising (i) a central portion adapted for direct application to a wound or bleeding site; and (ii) attached to an area in continuous and spaced relation to the wound or bleeding site, A central portion of the bandage, the bandage substantially including a strip adapted to be applied to a contoured or flexible body portion without wrinkling and to ensure secure attachment. A bandage comprising a hemostatic zone comprising a suitable matrix having a hemostatic-promoting amount of a hemostatic agent effective to accelerate blood coagulation and clot formation at the interface between the wound or bleeding site surface and the central portion of the bandage. 38. The hemostatic agent comprises a hemostatic polymer composition comprising a reaction product of an uncharged substance containing an organic hydroxyl group and a bifunctional substance containing at least one of a halogen atom or an epoxy group. 38. The bandage of claim 37, wherein the substance is reactive with organic hydroxyl groups of the uncharged substance. 39. The method of claim 38, wherein the hemostatic polymer composition is in dry form. 40. A method of stopping bleeding from a wound, comprising applying the bandage of claim 37 to a damaged surface. 41. A strip comprising: (a) a flexible substrate sheet and a strip comprising the dry sterile wound dressing of claim 1 carried on said strip; and (b) protection enclosing the strip. A dry, detachable wound healing pouch containing layers. 42. A method of temporarily stopping bleeding in a wound or bleeding, comprising: (i) applying a separation matrix to the wound or bleeding site; (ii) an effective amount of the separation matrix. A method comprising applying a hemostatic-promoting amount of a hemostatic agent to cover a wound or bleeding site, and (iii) removing the separation matrix and the hemostatic agent after bleeding has stopped or stopped at the wound or bleeding site. 43. The hemostatic agent comprises a dry hemostatic polymer composition comprising a reaction product of an uncharged substance containing an organic hydroxyl group and a bifunctional substance containing at least one of a halogen atom or an epoxy group. 43. The method of claim 42, wherein the functional material is reactive with organic hydroxyl groups. 44. A method of cleaning a wound at a bleeding or wound site, comprising applying the dry wound dressing of claim 1 to the surface of the bleeding or wound site for a period sufficient to cleanse the wound site. Including the hemostatic zone of the dry wound dressing is reactive with the local environment of the surface of the wound or bleeding site, thereby causing excess fluid, bacteria and exudate prior to the formation of coagulum at said wound or bleeding site. How to aspirate from the environment. 45. A method of treating a wound or bleeding site in a mammal comprising applying to the wound or bleeding site a therapeutically effective amount of a hemostatic polymer composition, the hemostatic polymer composition comprising: A reaction product of an uncharged substance containing an organic hydroxyl group and a bifunctional substance containing at least one of a halogen atom or an epoxy group, the bifunctional substance being reactive with the organic hydroxyl group of the uncharged substance. Method. 46. The method according to claim 45, wherein the substance containing an uncharged hydroxyl group is a carbohydrate, a polysaccharide or a polyol. 47. The carbohydrate is sucrose or sorbitol.
The method described. 48. The method of claim 46, wherein the polysaccharide is dextran, starch, alginate or cellulose. 49. The method of claim 46, wherein the polyol is polyvinyl alcohol.
The method described. 50. The method according to claim 45, wherein the substance containing a halogen atom is epichlorohydrin or dichlorohydrin. 51. The method of claim 45, wherein the material containing epoxy groups is diepoxybutane, diepoxypropyl ether or ethylene-glyco-bis-epoxypropyl ether. 52. The method of claim 45, comprising inducing hemagglutination and hemostasis at the wound or bleeding site without the addition of exogenous thrombin. 53. The method of claim 45, comprising inducing hemagglutination and hemostasis by contacting the hemostatic polymer composition with arterial blood flow. 54. The method of claim 45, comprising inducing hemagglutination and hemostasis by contacting the hemostatic polymer composition with venous blood flow. 55. At the wound or bleeding site, comprising attracting and activating platelets and coagulation factors normally found in blood with a hemostatic polymer composition.
4. The method described in 4. 56. The method of claim 54, comprising concentrating blood fibrinogen within the bleeding site with the hemostatic polymer composition. 57. The method of claim 45, wherein the hemostatic polymer composition further comprises collagen, fibrinogen or thrombin. 58. The method of claim 45, wherein the hemostatic polymer features a hemostatic cascade reaction zone. 59. A method of promoting hemagglutination and hemostasis, comprising administering to a wound or bleeding site a hemostatic polymer composition in combination with a pharmaceutically effective carrier or diluent. The composition comprises a reaction product of an uncharged substance containing an organic hydroxyl group and a difunctional substance containing at least one of a halogen atom or an epoxy group, the difunctional substance being reactive with the organic hydroxyl group of the uncharged substance. How to be. 60. The method of claim 59, wherein the hemostatic polymer composition is administered by delivery of an aerosol suspension. 61. A pharmaceutical composition useful for the rapid induction of hemagglutination and hemostasis, comprising a therapeutically effective amount of a hemostatic polymer in combination with a pharmaceutically acceptable carrier or diluent. Includes a reaction product of an uncharged substance containing an organic hydroxyl group and a difunctional substance containing at least one of a halogen atom or an epoxy group, the difunctional substance being reactive with the organic hydroxyl group of the uncharged substance. object. 62. A bandage or dressing for inducing rapid blood coagulation and hemostasis, comprising a reaction product of an uncharged substance containing an organic hydroxyl group and a bifunctional substance containing at least one halogen atom or epoxy group. A bandage or dressing comprising a therapeutically effective amount of a hemostatic polymer, the bifunctional material being reactive with the organic hydroxyl groups of the uncharged material. 63. A foam product useful for inducing rapid blood coagulation and hemostasis, the reaction of an uncharged substance containing an organic hydroxyl group with a bifunctional substance containing at least one halogen atom or epoxy group. A foam product comprising a therapeutically effective amount of a hemostatic polymer containing product, wherein the bifunctional material is reactive with the organic hydroxyl groups of the uncharged material. 64. A wound dressing for inducing rapid blood coagulation and hemostasis, which is a reaction product of an uncharged substance containing an organic hydroxyl group and a bifunctional substance containing at least one of a halogen atom or an epoxy group. A dressing comprising a therapeutically effective amount of a hemostatic polymer, the bifunctional material being reactive with the organic hydroxyl groups of the uncharged material. 65. The wound dressing of claim 64, which is in the form of a gel. 66. A hemostatic polymer comprising a hemostatic polymer in combination with a pharmaceutically acceptable carrier or diluent, said hemostatic polymer comprising an uncharged substance containing an organic hydroxyl group and at least one of a halogen atom or an epoxy group. A hemagglutinating wound healing composition comprising a reaction product with a substance, wherein said bifunctional substance is reactive with said organic hydroxyl group of said uncharged substance. 67. A compartmentalized kit comprising a hemostatic polymer composition, wherein the hemostatic polymer composition is the reaction of an uncharged material containing an organic hydroxyl group with a bifunctional material containing at least one halogen atom or epoxy group. A product, wherein the bifunctional material is reactive with the organic hydroxyl groups of the uncharged material,
kit.